Quinolylpropylpiperidine derivatives, their preparation, and compositions containing them

ABSTRACT

Quinolylpropylpiperidine derivatives of general formula (I) are described, and are useful as antimicrobial agents. Their preparation is also described.

[0001] This application claims priority benefit of French PatentApplication No. 01 03374, filed Mar. 13, 2001, and U.S. ProvisionalApplication No. 60/281,407 filed Apr. 5, 2001, both of which areincorporated herein by reference.

[0002] One embodiment of the present invention relates toquinolyl-propylpiperidine derivatives of general formula (I):

[0003] which are active as antimicrobials. Other embodiments of theinvention relate to their preparation and to compositions containingthem.

[0004] Patent Application Publications WO 99/37635 and WO 00/43383describe antimicrobial quinolylpropylpiperidine derivatives of generalformulas:

[0005] In which the radical R₁ may be (C₁₋₆)alkoxy; R₂ is hydrogen; R₃is at the 2- or 3-position and represents (C₁₋₆)alkyl, which may beoptionally substituted with 1 to 3 substituents chosen from thiol,halogen, alkylthio, trifluoromethyl, carboxyl, alkyloxycarbonyl,alkylcarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, hydroxyl optionallysubstituted with alkyl, and the like; R₄ is a group —CH₂—R₅, wherein R₅is selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl,phenylalkyl, which is optionally substituted, phenylalkenyl, which isoptionally substituted, heteroarylalkyl, which is optionallysubstituted, heteroaryl, which is optionally substituted, and the like;n is 0 to 2; m is 1 or 2; A and B may beoxygen, sulfur, sulfinyl,sulfonyl, NR₁₁, CR₆R₇, wherein R₆ and R₇ represent H, thiol, alkylthio,halo, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxyl, or amino; andZ₁ to Z₅ are N or CR_(1a), and the like.

[0006] European Patent Application EP30044 describes quinolinederivatives that are useful as cardiovascular agents and that correspondto the general formula:

[0007] in which R₁ may be alkyloxy; A—B is —CH₂—CH₂—, —CHOH—CH₂—,—CH₂—CHOH—, —CH₂—CO— or —CO—CH₂—; R₁ is H, OH, or alkyloxy; R₂ is ethylor vinyl; R₃ may be alkyl, hydroxyalkyl, cycloalkyl, hydroxyl, alkenyl,alkynyl, tetrahydrofuryl, phenylalkyl, diphenylalkyl, which isoptionally substituted, phenylalkenyl, which is optionally substituted,benzoyl, or benzoylalkyl, which is optionally substituted, heteroaryl orheteroaryl-alkyl, which is optionally substituted; and Z is H or alkylor forms with R₃ a cycloalkyl radical.

[0008] The inventors have now found that the compounds of formula (I)are potent antibacterial agents. In the compounds of formula (I),

[0009] R₁ represents a hydrogen atom, a halogen atom, or a hydroxyl,amino, alkylamino, dialkylamino, hydroxyamino, alkyloxyamino, oralkylalkyloxyamino radical;

[0010] R₂ represents a carboxyl, carboxymethyl, or hydroxymethylradical;

[0011] R₃ represents an alkyl radical containing 1 to 6 carbon atoms,substituted with a phenylthio radical, which may itself carry 1 to 4substituents chosen from halogen, hydroxyl, alkyl, alkyloxy,trifluoromethyl, trifluoro-methoxy, carboxyl, alkyloxycarbonyl, cyano,and amino, or substituted with a cycloalkylthio radical in which thecyclic portion contains 3 to 7 members, or substituted with a 5- to6-membered aromatic heterocyclylthio radical comprising 1 to 4heteroatoms chosen from nitrogen, oxygen, and sulfur, and itselfoptionally substituted with halogen, hydroxyl, alkyl, alkyloxy,trifluoromethyl, trifluoro-methoxy, oxo, carboxyl, alkyloxycarbonyl,cyano, or amino; or

[0012] R₃ represents a propargyl radical substituted with a phenylradical, which may itself be substituted with 1 to 4 substituents chosenfrom halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl,trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, and amino, orsubstituted with a 3- to 7-membered cycloalkyl radical or substitutedwith a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4heteroatoms chosen from nitrogen, oxygen and sulfur, and itselfoptionally substituted with halogen, hydroxyl, alkyl, alkyloxy,trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl,cyano, or amino; and

[0013] R₄ represents an alkyl radical (containing 1 to 6 carbon atoms),alkenyl-CH₂—, alkynyl-CH₂— (in which the alkenyl or alkynyl portionscontain 2 to 6 carbon atoms), cycloalkyl or cycloalkylalkyl radical (inwhich the cycloalkyl portion contains 3 to 8 carbon atoms).

[0014] The compounds of the invention include the diastereoisomericforms of the compounds of formula (I), their mixtures, and their cis ortrans forms, as well as their salts.

[0015] It is understood that the alkyl radicals and alkyl portions ofthe compounds of the invention may be in the form of a straight orbranched chain and contain, unless otherwise stated, 1 to 4 carbonatoms, and that in the alternative case where R₁ represents a halogenatom or when R₃ carries a halogen substituent, the latter may be chosenfrom fluorine, chlorine, bromine, and iodine.

[0016] Other than in the working examples, or where otherwise indicated,all numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe present invention. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques.

[0017] Notwithstanding that the numerical ranges and parameters settingforth the broad scope of the invention are approximations, the numericalvalues set forth in the working examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

[0018] In formula (I), when R₃ carries an aromatic heterocyclylsubstituent, the latter may be chosen, without limitation, from thienyl,furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, andpyrimidinyl.

[0019] According to the invention, the compounds of formula (I) may beobtained by condensing an R₃ radical with a quinolylpropylpiperidinederivative of formula (II):

[0020] in which R₄ is as defined above for compounds of formula (I), R′₁represents a hydrogen atom or a hydroxyl radical, and R′₂ represents aprotected carboxyl or carboxymethyl radical, to obtain aquinolylpropylpiperidine derivative of formula (III):

[0021] for which R′₁, R′₂, R₃, and R₄ are as defined above.

[0022] Where appropriate, this reaction may be followed by either a) thehalogenation of a derivative for which R′₁ is a hydroxyl radical, if itis desired to obtain a quinolylpropylpiperidine derivative for which R₁is a halogen atom, or b) the conversion of a hydroxyl radical to an oxoradical, and then to a hydroxyimino or alkyloxyimino radical accordingto known methods which do not adversely affect the rest of the molecule,to obtain a quinolylpropylpiperidine derivative of formula (IV):

[0023] for which R′₂, R₃, and R₄ are as defined above, and R₅ is ahydrogen atom or an alkyl radical. Where appropriate or desired, thisreaction may be followed by: a) the reduction of a derivative of formula(IV) for which R₅ is a hydrogen atom to an amine, and optionally by theconversion to a monoalkylated or dialkylated amine; b) the reduction ofthe derivative of formula (IV) for which R₅ is a hydrogen atom to ahydroxylamine; c) the reduction of a derivative of formula (IV) forwhich R₅ is an alkyl radical to an alkyloxyamine, and then, whereappropriate to obtain a derivative for which R₁ is alkylalkyloxy-amino,the derivative obtained for which R₁ is alkyl-oxyamino can be convertedby alkylation, and/or d) the reduction of a protected carboxyl radicalR′₂ to a hydroxymethyl radical according to known methods that do notadversely affect the rest of the molecule. The final step can beoptionally followed by the separation of the diastereoisomers, by theseparation of the cis and trans forms, by removal, where appropriate, ofthe acid-protecting radical, and/or by the conversion of the finalreaction product obtained to a salt.

[0024] The condensation of an R₃ radical with piperidine may be carriedout by the action of a derivative of formula (V):

R₃—X  (V)

[0025] in which R₃ is as defined above and X represents a halogen atom,a methylsulfonyloxy radical, a trifluoro-methylsulfonyloxy radical, or ap-toluenesulfonyloxy radical. The reaction may be carried out, forexample, in an anhydrous, inert medium (nitrogen or argon, for example),in an organic solvent such as an amide (dimethylformamide, for example),a ketone (acetone, for example) or a nitrile (acetonitrile, for example)in the presence of a base such as a nitrogen-containing organic base(for example, triethylamine), or an inorganic base (alkali metalcarbonate:potassium carbonate, for example) at a temperature rangingfrom 20° C. to the reflux temperature of the solvent.

[0026] Examples of derivatives of formula (V) include those for which Xis a bromine or an iodine atom.

[0027] When R₃ represents propargyl substituted with phenyl, cycloalkyl,or heterocyclyl, a propargyl halide may be condensed, and then the chainmay be substituted with a phenyl, cycloalkyl or heterocyclyl radical. Inthis alternative case, the addition of the propargyl chain may becarried out, for example, by means of propargyl bromide, under theconditions set out above for R₃ in the presence or in the absence of analkali metal iodide such, as for example, potassium or sodium iodide.

[0028] When substitution with a phenyl or heterocyclyl radical isinvolved, the reaction may be carried out by the action of a halidederived from the cyclic radical to be substituted, in the presence oftriethylamine, in anhydrous medium, optionally with no solvent or in asolvent such as an amide (dimethyl-formamide, for example) or a nitrile(acetonitrile, for example) and in the presence of a palladium salt suchas, for example, tetrakis(triphenylphosphine)palladium and copper(I)iodide, at a temperature ranging from 20° C. to the reflux temperatureof the solvent.

[0029] When substitution with a cycloalkyl group is involved, thereaction may be carried out by the action of an organolithium compoundsuch as n-butyllithium or tert-butyllithium on the propargyl derivativeobtained above, in anhydrous medium in an ether such as, for example,tetrahydrofuran at a temperature ranging from −78 to 0° C., followed bythe action of a cycloalkanone and then by the deoxygenation of theintermediate alcohol according to conventional methods.

[0030] It is understood that when the alkyl radicals represented by R₃carry carboxyl or amino substituents, the latter can be protectedbeforehand and then released after the reaction. The procedure can becarried out according to customary methods which do not adversely affectthe rest of the molecule, for example, according to the methodsdescribed by T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis (2nd ed.), A. Wiley-Interscience Publication (1991),or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press(1973), both of which are hereby incorporated herein by reference.

[0031] The protected carboxyl or carboxymethyl radical represented byR₁₂ may be chosen from an easily hydrolyzable ester. These estersinclude, for example, methyl, benzyl, tert-butyl esters, allyl, orphenylpropyl esters. Optionally, the carboxyl radical may be protectedsimultaneously with the reaction. In this case, the derivative offormula (II) used carries a radical R′₂=carboxyl or carboxymethyl.

[0032] The halogenation intended to obtain a quinolylpropylpiperidinederivative for which R₁ is a halogen atom, from the derivative for whichR′₁ is hydroxyl, may be carried out in the presence of an aminosulfurtrifluoride (diethylaminosulfur trifluoride,bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor®), ormorpholinosulfur trifluoride, for example) or alternatively in thepresence of sulfo tetrafluoride. The fluorination reaction may also becarried out by the action of a fluorinating agent such as a sulfurfluoride [for example, morpholinosulfur trifluoride, sulfurtetrafluoride (J. Org. Chem., 40, 3808 (1975), which is herebyincorporated by reference), diethylaminosulfur trifluoride (Tetrahedron,44, 2875 (1988)), bis(2-methoxyethyl)aminosulfur trifluoride(Deoxofluor®). Alternatively, the fluorination reaction may also becarried out by means of a fluorinating agent such ashexafluoropropyldiethylamine (See JP 2 039 546) orN-(2-chloro-1,1,2-trifluoroethyl)diethylamine. The halogenation reactionmay also be carried out using a reagent such as a tetraalkylammonium,trialkylbenzyl-ammonium, or trialkylphenylammonium halide or using analkali metal halide optionally substituted with a crown ether.

[0033] When a tetraalkylammonium halide is used, the latter may bechosen, by way of example, from tetra-methylammonium,tetraethylammonium, tetrapropyl-ammonium, tetrabutylammonium(tetra-n-butylammonium, for example), tetrapentylammonium,tetracyclohexylammonium, triethylmethylammonium, tributylmethylammonium,and trimethylpropylammonium halides.

[0034] The procedure may be carried out in an organic solvent such as achlorinated solvent (for example, dichloromethane, dichloroethane, orchloroform) or in an ether (tetrahydrofuran or dioxane, for example) ata temperature ranging from −78 to 40° C., for example, from 0 to 30°C.). It is advantageous to carry out the procedure in an inert medium,argon or nitrogen, for example.

[0035] It is also possible to carry out the procedure by treatment witha halogenating agent such as thionyl chloride or phosphorus trichloridein an organic solvent such as a chlorinated solvent (dichloromethane orchloroform, for example), at a temperature ranging from 0° C. to thereflux temperature of the reaction mixture.

[0036] The conversion of the hydroxyl radical to an oxo radical may becarried out using conventional oxidation methods described in theliterature, such as in D. Swern oxidation, J.O.C., 44, 41-48 (1979),which is hereby incorporated by reference, for example, in the presenceof oxalyl chloride and of dimethyl sulfoxide, optionally in a solventsuch as dichloromethane, or without solvent, at a temperature rangingfrom −60 to 20° C., followed by the conversion of the oxo radical to ahydroxyimino or alkyloxyimino radical.

[0037] The conversion of the oxo radical to a hydroxyimino oralkyloxyimino radical may be carried out by the action of hydroxylamine(hydroxylamine hydrochloride, for example) or of alkyloxyamine,optionally in hydrochloride form, in a solvent such as pyridine or analcohol (such as methanol or ethanol, for example) and in the presenceof a nitrogen base such as triethylamine or pyridine at a temperatureranging from 0 to 60° C.

[0038] The reduction of a derivative of formula (IV), for which R₅ ishydrogen, to an amine may be carried out according to customary methodsthat do not adversely affect the rest of the molecule, for instance, bythe action of a reducing agent such as, for example, a hydride (alkalimetal borohydride, such as sodium or potassium borohydride; or aluminumand lithium hydride) in the presence or in the absence of molybdenumoxide, the procedure may be carried out under an inert atmosphere(nitrogen or argon, for example), in an organic solvent such as analcohol (methanol, ethanol or isopropanol, for example) or a chlorinatedsolvent (for example, dichloromethane) at a temperature ranging from −10to 40° C.

[0039] The reduction of a derivative of formula (IV) to a hydroxylamineor to an alkyloxyamine may be carried out, for example, in the presenceof an organic acid (carboxylic acid such as, for example, acetic acid),by the action of a reducing agent such as, for example, a hydride chosenfrom sodium triacetoxy-borohydride (optionally prepared in situ) orsodium cyanoborohydride. In one embodiment of the invention, thisreaction is carried out under an inert atmosphere (nitrogen or argon,for example), in an organic solvent such as an alcohol (methanol,ethanol or isopropanol, for example) or a chlorinated solvent (forexample, dichloromethane) at a temperature ranging from −30 to +40° C.

[0040] The conversion of the amino radical represented by R₁ to analkylamino or dialkylamino radical may be carried out according tocustomary methods, for example, by the action of an alkyl halide,optionally in a basic medium in the presence of a nitrogen base such asa trialkylamine (triethylamine, diisopropylethylamine, and the like),pyridine, or in the presence of an alkali metal hydride (sodiumhydride), in an inert solvent such as an amide (dimethylformamide, forexample) or an oxide (dimethyl sulfoxide, for example), at a temperatureranging from 20° C. to the reflux temperature of the reaction medium.

[0041] The conversion of the alkyloxyamino radical represented by R₁ toan alkylalkyloxyamino radical may be carried out according to the methoddescribed above for the alkylation of the amine.

[0042] The removal, where appropriate, of the acid-protecting radical toobtain a quinolylpropylpiperdine derivative for which R₂ is a carboxylor carboxymethyl radical may be carried out according to the usualmethods, for example, by acid hydrolysis or saponification of the esterR′₂. For instance, sodium hydroxide may be caused to act in anaqueous-organic medium, for example in an alcohol such as methanol or anether such as dioxane, at a temperature ranging from 20° C. to thereflux temperature of the reaction mixture. It is also possible to usehydrolysis in aqueous hydrochloric medium at a temperature ranging from20 to 100° C.

[0043] Where appropriate, a derivative of formula (I) for which R₂ ishydroxymethyl may be prepared from a derivative for which R′₂ isprotected carboxyl. For example, the procedure may be carried out byreducing the product protected in the form of an ester R′₂, according tothe customary methods that do not adversely affect the rest of themolecule, for example, by the action of a hydride (aluminum and lithiumhydride or diisobutylaluminum hydride, for example) in a solvent such asan ether (tetrahydrofuran, for example) at a temperature ranging from 20to 60° C.

[0044] A quinolylpropylpiperidine derivative of formula (II) for whichR′₂ represents a protected carboxymethyl radical, and R′₁ is a hydrogenatom, may be prepared by selective hydrogenation of aquinolylpropylpiperidine derivative of formula (VI):

[0045] in which R₄ is as defined above and R′₂ is the protected carboxylradical corresponding to R′₂, and in which the amine functional group ofthe piperidine is protected beforehand, at a pressure between 1 to 100bar and at a temperature ranging from 20 to 80° C., in a solvent suchas, for example, an alcohol (ethanol, for example) or an amide(dimethylformamide, for example) in the presence of a catalyst, forexample, palladium on carbon or palladium on barium sulfate.

[0046] The protection of the amino group of the piperidine may becarried out according to customary methods that do not adversely affectthe rest of the molecule and that are compatible with the reaction, forexample, according to the references cited above. In one embodiment ofthe invention, the protective radical is the benzyloxycarbonyl radical.In this case, the hydrogenation reaction leads directly to thedeprotection of the amine.

[0047] A quinolylpropylpiperidine derivative of formula (VI) may beprepared by condensing a quinoline derivative of formula (VII):

[0048] in which R₄ is as defined above and Hal represents an iodine orbromine atom, with a piperidine derivative of formula (VIII):

[0049] in which R″₂ is as defined above and R_(z) represents anamino-protecting radical.

[0050] The reaction may be carried out by the successive action of anorganoborane (9-borabicyclo[3.3.1]nonane, for example) in a solvent suchas an ether (tetrahydrofuran or dioxane, for example) at a temperatureranging from −20 to 20° C., followed by the addition of a quinolinederivative of formula (VII), by analogy with the methods described bySuzuki et al., Pure and Appl. Chem., 57, 1749 (1985), which is herebyincorporated by reference. The reaction is generally carried out in thepresence of a palladium salt (palladiumdiphenylphosphinoferrocenechloride, for example) and of a base such as potassium phosphate, at atemperature ranging from 20° C. to the reflux temperature of thesolvent.

[0051] A piperidine derivative of formula (VIII) may be prepared by theWittig reaction, by condensing a phosphorus ylide with a piperidinederivative of formula (IX):

[0052] in which Rz is as defined above.

[0053] In one embodiment of the invention, the procedure is carried outusing methyl (triphenylphosphoranylidene)acetate, in a solvent such as,for example, toluene, at a temperature ranging from 20 to 110° C.

[0054] The 3-oxopiperidine derivative of formula (IX) may be preparedaccording to or by analogy with the method described by Y. Takeuchi etal., Synthesis, 10, 1814 (1999), which is hereby incorporated byreference.

[0055] The quinolylpropylpiperidine derivative of formula (II), forwhich R′₂ is a carboxyl radical and R′₁ is a hydrogen atom, may beprepared from the corresponding derivative for which R′₂ is protectedcarboxymethyl, by reducing this radical to an alcohol, converting to ap-toluenesulfonyloxy derivative, and then converting this derivative toa vinyl derivative by an elimination reaction followed by the oxidationof the derivative obtained.

[0056] According to another embodiment of the invention, aquinolylpropylpiperidine derivative of formula (II), for which R′₂ is acarboxyl radical and R′₁ is a hydrogen atom, may be prepared bycondensing a quinoline derivative of formula (VIII) as defined above,with a piperidine derivative of formula (X):

[0057] in which Rz is as defined above, and R′₂ represents a protectedcarboxyl radical as defined above, followed by removal of theamino-protecting radical Rz.

[0058] The reaction can be carried out under conditions similar to theconditions described for the reaction of the quinoline derivative offormula (VII) and of a piperidine derivative of formula (VIII). Theelimination of the radical Rz can be carried out according to themethods cited above, according to the examples, or as described by T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (2nded.), A. Wiley-Interscience Publication (1991), or by Mc Omie,Protective Groups in Organic Chemistry, Plenum Press (1973).

[0059] A compound of formula (X) may be prepared according to or byanalogy with the method described below in the examples.

[0060] The reduction, in alcohol, of the acid protected in the form of aradical R′₂ at the 3-position of the piperidine, to a hydroxyethylradical can be carried out according to customary methods that do notadversely affect the rest of the molecule, for example, the procedurecan be carried out by the action of a hydride (lithium and aluminumhydride or diisobutylaluminum hydride, for example) in a solvent such asan ether (tetrahydrofuran, for example) at a temperature ranging from 20to 60° C.

[0061] The conversion of a quinolylpropyl-piperidine derivative forwhich R′₂ is hydroxyethyl to a p-toluenesulfonyloxyethyl derivative canbe carried out, for example, according to the method described by L. F.Fieser and M. Fieser, Reagents for Organic Synthesis, vol. 1, 1179(1967), which is hereby incorporated by reference, starting withp-toluenesulfonyl chloride in the presence of a base such as a tertiaryamine (for example, triethylamine) or an aromatic amine (for example,pyridine), in a halogenated solvent (for example, dichloromethane) orwithout solvent, at a temperature ranging from 0 to 50° C.

[0062] The conversion of the p-toluenesulfonyloxy-ethyl derivative to avinyl derivative can be carried out by an elimination reaction, forexample, according to the method described by A. Sharma et al., Org.Prep Proced. Int., 25(3), 330-333 (1993), which is hereby incorporatedby reference, in the presence of a base such as, for example, potassiumt-butoxide in a solvent such as dimethylsulfoxide, for example, at atemperature ranging from 20 to 100° C.

[0063] The conversion of a vinyl derivative to a derivative for whichR′₂ is carboxyl is carried out by the oxidation methods described in theliterature, for example, using sodium metaperiodate in the presence ofruthenium trichloride hydrate, in a mixture of solvents such as, forexample, the water/acetonitrile mixture, at a temperature ranging from20 to 60° C.

[0064] A quinolylpropylpiperidine derivative of formula (II) for whichR′₁ is a hydroxyl radical may be prepared by oxidizing, in a basicmedium, the corresponding derivative for which R′₁ is a hydrogen atom.The oxidation is carried out by the action of oxygen, for example, in aninert solvent such as dimethyl sulfoxide, in the presence oftert-butanol and a base such as potassium or sodium tert-butoxide, at atemperature ranging from 0 to 100° C.

[0065] The quinoline derivatives of formula (VII) for which Hal is aniodine atom may be prepared by analogy with the work by E. Arzel et al.,Tetrahedron, 55, 12149-12156 (1999), which is hereby incorporated byreference, from 3-fluoro-6-methoxyquinoline, by the successive action ofa base and then of iodine. Lithium diisopropylamide may be used, forexample, in a solvent such as an ether (tetrahydro-furan) at atemperature ranging from −80 to 20° C. The 3-fluoro-3-methoxyquinolinemay be obtained by pyrolysis of 6-methoxyquinoline diazonium3-tetra-fluoroborate or 3-hexafluorophosphate according to theBalz-Schieman reaction, Org. Synth., Coll 5, 133 (1973), which is herebyincorporated by reference, at a temperature ranging from 100 to 240° C.The 6-methoxyquinoline diazonium 3-tetrafluoroborate or6-methoxyquinoline diazonium 3-hexafluorophosphate may be obtained from3-amino-6-methoxyquinoline by the action of an alkali metal nitrite(sodium nitrite for example) in an acid medium (tetrafluoroboric acid orhexafluorophosphoric acid) in a solvent such as water, at a temperatureranging from −10 to +20° C., by analogy with the work by A. Roe et al.,J. Am. Chem. Soc., 71, 1785-86 (1949), which is hereby incorporated byreference or by the action of an alkyl nitrite (such as, for example,isoamyl nitrite) and of the complex of diethyl ether trifluoroborate ina solvent such as an ether (tetrahydrofuran, for example) at atemperature ranging from −10 to +10° C. The 3-amino-6-methoxyquinolinecan be prepared as described by N. Heindel, J. Med. Chem., 13, 760(1970), which is hereby incorporated by reference. The quinolinederivative of formula (VII) for which Hal is a bromine atom may also beprepared by analogy with this method.

[0066] The intermediates of the quinolylpropyl-piperidine derivativesfor which R₄ represents alkenyl-CH₂—, alkynyl-CH₂—, cycloalkyl orcycloalkyl-alkyl may be obtained by analogy with the preparation of theintermediates for which R₄ is alkyl, by the action of the correspondinghalogenated derivative on the quinoline derivative hydroxylated at the6-position.

[0067] It is understood that the derivatives of formula (I), (II),(III), (IV) and their starting intermediates may exist in the cis ortrans form at the level of the substituents at the 3- and 4-position ofpiperidine. The derivatives of the trans configuration may be obtainedfrom the derivatives of the cis configuration according to or by analogywith the method described in International Application WO 99/37635,which method is hereby incorporated by reference.

[0068] The quinolylpropylpiperdine derivatives of formula (I) may bepurified, where appropriate, by physical methods such as crystallizationor chromatography.

[0069] Moreover, it is understood that when R₁ is other than a hydrogenatom, diastereoisomeric forms may exist and that the diastereoisomericforms and mixtures thereof also fall within the scope of the presentinvention. Diastereoisomeric mixtures may be separated, for example, bychromatography on silica or by High-Performance Liquid Chromatography(HPLC). Likewise, the cis and trans derivatives may be separated bychromatography on silica or by High-Performance Liquid Chromatography(HPLC).

[0070] The quinolylpropylpiperidine derivatives of formula (I) may beconverted to addition salts with acids by known methods. It isunderstood that these salts also fall within the scope of the presentinvention.

[0071] Examples of addition salts with pharmaceutically acceptable acidsinclude the salts formed with inorganic acids (for example,hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates) orwith organic acids (for example, succinates, fumarates, tartrates,acetates, propionates, maleates, citrates, methanesulfonates,ethanesulfonates, phenyl-sulfonates, p-toluenesulfonates, isethionates,naphthylsulfonates, and camphorsulfonates, or with the substitutionderivatives of these compounds).

[0072] Some of the quinolylpropylpiperidine derivatives of formula (I)carrying a carboxyl radical may be converted to the form of metal saltsor to addition salts with the nitrogen bases according to methods knownper se. These salts also fall within the scope of the present invention.The salts may be obtained by the action of a metal base (for example, analkali or alkaline-earth metal), ammonia or an amine, on a productaccording to the invention, in an appropriate solvent such as analcohol, an ether, or water, or by an exchange reaction with a salt ofan organic acid. The salt formed precipitates after optionalconcentration of the solution, it may be separated by filtration,decantation, or freeze-drying. Examples of pharmaceutically acceptablesalts include the salts formed with alkali metals (sodium, potassium,lithium) or alkaline-earth metals (magnesium, calcium), the ammoniumsalt, and the salts of nitrogen bases (ethanolamine, diethanolamine,trimethylamine, triethylamine, methylamine, propylamine,diisopropylamine, N,N-dimethylethanol-amine, benzylamine,dicyclohexylamine, N-benzyl-β-phenethylamine,N,N′-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine,quinine, chlorine, arginine, lysine, leucine, and dibenzylamine).

[0073] The quinolylpropylpiperidine derivatives according to theinvention are useful advantageous antibacterial agents.

[0074] In vitro, on gram-positive microbes, the quinolylpropylpiperidinederivatives according to the invention have proved active atconcentrations ranging from 0.03 to 4 μg/ml on meticillin-resistantStaphylococcus aureus AS5155, also at concentrations ranging from 0.06to 8 μg/ml on Streptococcus pneumoniae 6254-01 and at concentrationsranging from 0.06 to 64 μg/ml on Enterococcus faecium H983401. Ongram-negative microbes they have proved active at concentrations rangingfrom 0.32 to 32 μg/ml on Moraxella catharrhalis IPA152; in vivo, theyhave proved active on experimental infections of mice withStraphylococcus aureus IP8203 at doses ranging from 12 to 150 mg/kg bythe subcutaneous route (CD50) and for some of them at doses ranging from26 to 150 mg/kg by the oral route.

[0075] Finally, the compounds according to the invention are also usefulbecause of their low toxicity to the host. None of the compoundsexhibited toxicity at the dose of 100 mg/kg by the subcutaneous route inmice (2 administrations).

[0076] Examples of the quinolylpropylquinoline derivatives of theinvention include:

[0077] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-carboxylicacid

[0078] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0079] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0080] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0081] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0082] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)propyl]piperidine-3-carboxylicacid

[0083] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-carboxylicacid

[0084] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-carboxylicacid

[0085] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-carboxylicacid

[0086] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylicacid

[0087] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylicacid

[0088] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-carboxylicacid

[0089] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluorothien-2-yl)thioethyl]piperidine-3-carboxylicacid

[0090] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-carboxylicacid

[0091] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-carboxylicacid

[0092] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-carboxylicacid

[0093] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluoropyridin-2-yl)thioethyl]piperidine-3-carboxylicacid

[0094] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0095] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0096] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]-piperidine-3-carboxylicacid

[0097] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0098] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-carboxylicacid

[0099] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-carboxylicacid

[0100] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-carboxylicacid

[0101] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0102] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0103] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0104] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0105] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)ethyl]piperidine-3-carboxylicacid

[0106] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-carboxylicacid

[0107] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-carboxylicacid

[0108] (3RS,4 RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-carboxylicacid

[0109] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylicacid

[0110] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylicacid

[0111] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluorothien-2-yl)thioethyl]piperidine-3-carboxylicacid

[0112] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-carboxylicacid

[0113] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-carboxylicacid

[0114] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluoropyridin-2-yl)thioethyl]piperidine-3-carboxylicacid

[0115] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-carboxylicacid

[0116] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0117] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]-piperidine-3-carboxylicacid

[0118] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0119] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0120] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-carboxylicacid

[0121] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-carboxylicacid

[0122] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0123] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0124] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylicacid

[0125] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylicacid

[0126] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-carboxylicacid

[0127] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-carboxylicacid

[0128] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-carboxylicacid

[0129] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluoro-phenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0130] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0131] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-carboxylicacid

[0132] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-carboxylicacid

[0133] (3RS,4RS) or(3SR,4RS)₄-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0134] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0135] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0136] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-carboxylicacid

[0137] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)propyl]piperidine-3-carboxylicacid

[0138] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-carboxylicacid

[0139] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-carboxylicacid

[0140] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-carboxylicacid

[0141] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylicacid

[0142] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylicacid

[0143] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-carboxylicacid

[0144] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluorothien-2-yl)thioethyl]piperidine-3-carboxylicacid

[0145] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-carboxylicacid

[0146] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-carboxylicacid

[0147] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-carboxylicacid

[0148] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-3-yl)thioethyl]piperidine-3-carboxylicacid

[0149] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0150] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0151] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0152] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylicacid

[0153] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-carboxylicacid

[0154] (3RS,4RS) or(3SR,4RS)₄-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)-prop-2-ynyl]piperidine-3-carboxylicacid

[0155] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-aceticacid

[0156] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-aceticacid

[0157] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-aceticacid

[0158] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-aceticacid

[0159] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-aceticacid

[0160] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)propyl]piperidine-3-aceticacid

[0161] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-aceticacid

[0162] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-aceticacid

[0163] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-aceticacid

[0164] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-aceticacid

[0165] (3RS,4RS) or(3SR,4RS)₄-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-aceticacid

[0166] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluoro-thien-2-yl)thioethyl]piperidine-3-aceticacid

[0167] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-aceticacid

[0168] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-aceticacid

[0169] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-aceticacid

[0170] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluoropyridin-2-yl)thioethyl]piperidine-3-aceticacid

[0171] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0172] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0173] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0174] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0175] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-aceticacid

[0176] (3RS,4RS) or(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-aceticacid

[0177] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-aceticacid

[0178] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-aceticacid

[0179] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-aceticacid

[0180] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-aceticacid

[0181] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)propyl]piperidine-3-aceticacid

[0182] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-aceticacid

[0183] (3RS,4RS) or(3SR,4RS)₄-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-aceticacid

[0184] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-aceticacid

[0185] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-aceticacid

[0186] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluorothien-2-yl)thioethyl]piperidine-3-aceticacid

[0187] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-aceticacid

[0188] (3RS,4RS) or(3SR,4RS)₄-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-aceticacid

[0189] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-aceticacid

[0190] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluoropyridin-2-yl)thioethyl]piperidine-3-aceticacid

[0191] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0192] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0193] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0194] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-aceticacid

[0195] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-aceticacid

[0196] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-aceticacid

[0197] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-aceticacid

[0198] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-aceticacid

[0199] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-aceticacid

[0200] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-aceticacid

[0201] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-aceticacid

[0202] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-aceticacid

[0203] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluoro-phenyl)prop-2-ynyl]piperidine-3-aceticacid

[0204] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0205] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)-prop-2-ynyl]piperidine-3-aceticacid

[0206] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-aceticacid

[0207] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-aceticacid

[0208] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-aceticacid

[0209] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-aceticacid

[0210] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)propyl]piperidine-3-aceticacid

[0211] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-aceticacid

[0212] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-aceticacid

[0213] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-aceticacid

[0214] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-aceticacid

[0215] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-aceticacid

[0216] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluoro-thien-2-yl)thioethyl]piperidine-3-aceticacid

[0217] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-aceticacid

[0218] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-aceticacid

[0219] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-aceticacid

[0220] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluoropyridin-2-yl)thioethyl]piperidine-3-aceticacid

[0221] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0222] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0223] (3RS,4RS) or(3SR,4RS)₄-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0224] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-aceticacid

[0225] (3RS,4RS) or(3SR,4RS)₄-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-aceticacid

[0226] (3RS,4RS) or(3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-aceticacid

[0227] as well as their salts.

[0228] The following examples illustrate the present invention but donot limit it.

EXAMPLE 1

[0229] a)(3RS,4RS)-4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)-propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-aceticAcid Dihydrochloride

[0230] A solution of 480 mg of methyl(3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-acetate,5 cm³ of dioxane and 2.25 cm³ of a 1 N aqueous sodium hydroxide solutionwas heated, with stirring, at a temperature in the region of 60° C. for1 hour 30 minutes. After concentrating the reaction mixture underreduced pressure (5 kPa) at a temperature the region of 40° C., theresidue obtained was taken up in 50 cm³ of water and 20 cm³ of ether.The aqueous phase was separated after settling out and then washed twicewith 10 cm³ of ether. It was then acidified by pouring 2.25 cm³ of 1 Nhydrochloric acid. The precipitate formed was dissolved by adding 75 cm³of dichloromethane. The organic phase was separated after settling out,dried over magnesium sulfate, filtered, and then concentrated underreduced pressure (5 kPa) at a temperature in the region of 40° C. Theproduct obtained was then stirred in 30 cm³ of acetone. 4 cm³ of 4 Nhydrochloric acid in dioxane were then poured over this solution. Thereaction mixture was concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. and then 15 cm³ of acetone wereadded. This operation was repeated 5 times until a yellow solid wasobtained, which solid was drained and then dried in a desiccator underreduced pressure (10 Pa) at a temperature of about 45° C. 395 mg of(3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-aceticacid dihydrochloride were obtained in the form of a solid, which wasoff-white in color.

[0231]¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 at a temperature of 393K, δin ppm): from 1.40 to 1.90 (mt: 7H); 2.29 (dd, J=16 and 5.5 Hz: 1H);2.46 (unresolved complex: 1H); from 2.65 to 3.45 (mt: 5H); 3.09 (broadt, J=7.5 Hz: 2H); 3.23 (broad s: 4H); 3.99 (s: 3H); 7.09 (dd, J=5.5 and3.5 Hz: 1H); 7.27 (dd, J=3.5 and 1.5 Hz: 1H); 7.38 (d, J=3 Hz: 1H); 7.40(dd, J=9 and 3 Hz: 1H); 7.62 (dd, J=5.5 and 1.5 Hz: 1H); 7.98 (d, J=9Hz: 1H); 8.64 (broad s: 1H).

[0232] b) Methyl(3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate

[0233] A suspension composed of 0.95 g of methyl (3RS,4RS) and(3SR,4RS)-4-[3-(3-fluoro-6-methoxy-quinolin-4-yl)propyl]piperidine-3-acetate,0.7 g of potassium carbonate, 0.68 g of 2-(2-bromoethylthio)-thiophenein 40 cm³ of dimethylformamide was stirred for 16 hours at a temperaturein the region of 60° C. under an inert atmosphere. After cooling toabout 20° C., the reaction mixture was poured over 200 cm³ of water and200 cm³ of ethyl acetate. The organic phase was separated after settlingout and then washed 5 times with 100 cm³ of water and then with 100 cm³of a saturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered, and then concentrated under reduced pressure (5 kPa)at a temperature in the region of 40° C. The evaporation residueobtained was purified by chromatography, under a nitrogen pressure of 50kPa, on a column of silica gel (particle size 20-45 μ; diameter 2 cm;height 40 cm), eluting with a cyclohexane-ethyl acetate (68/32 byvolume) mixture. 15-cm³ fractions were collected. Fractions 15 to 21were concentrated. 480 mg of methyl(3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-acetatewere obtained in the form of an orange-colored oil.

[0234]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.15 to1.70 (mt: 7H); from 1.90 to 2.05 (mt: 2H); 2.08 (unresolved complex:1H); 2.17 (broad dd, J=16 and 4 Hz: 1H); from 2.35 to 2.80 (mt: 5H);2.90 (mt: 2H); 3.07 (broad t, J=7.5 Hz: 2H); 3.57 (s: 3H); 3.97 (s: 3H);7.06 (dd, J=5.5 and 4 Hz: 1H); 7.17 (dd, J=4 and 1.5 Hz: 1H); 7.38 (d,J=3 Hz: 1H); 7.40 (dd, J=9 and 3 Hz: 1H); 7.62 (dd, J=5.5 and 1.5 Hz:1H); 7.97 (d, J=9 Hz: 1H); 8.70 (broad s: 1H).

[0235] c) Methyl (3RS,4RS) and(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate

[0236] 2.65 g of methyl(4RS)-1-benzyloxycarbonyl-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-ylideneacetate,Z isomer, 45 cm³ of absolute ethanol and 265 mg of 10% palladium oncarbon were introduced into an autoclave. The reaction mixture wasstirred under 5 bar of hydrogen at 22° C. for 24 hours and then filteredon supercel, and rinsed 5 times with 20 cm³ of absolute ethanol. Thecombined filtrates were concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. 1.85 g of methyl (3RS,4RS) and(3SR,4RS)-4-[3-(3-fluoro-6-methoxy-quinolin-4-yl)propyl]piperidine-3-acetatewere obtained in the form of a colorless oil.

[0237]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.10 to1.80 (mt: 7H); from 1.90 to 2.30 (mt: 2H); from 2.35 to 2.60 (mt: 3H);from 2.65 to 2.95 (mt: 2H); 3.06 (mt: 2H); 3.55 and 3.56 (2s: 3H intotal); 3.95 to 3.96 (2s: 3H in total); from 7.30 to 7.45 (mt: 2H); 7.96(d, J=9 Hz: 1H); 8.70 (broad s: 1H).

[0238] d) Methyl(4RS)-1-benzyloxycarbonyl-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-ylidenacetate,Z Isomer.

[0239] A solution of 5.8 g of methyl(4RS)-4-allyl-1-benzyloxycarbonylpiperidin-3-ylideneacetate (Z isomer)in 15 cm³ of tetrahydrofuran was slowly added, at a temperature in theregion of 0° C., with stirring and under an inert atmosphere, to 45 cm³of a 0.5 M 9-borabicyclo[3.3.1]nonane solution in tetrahydrofuran. Themixture was then brought to a temperature in the region of 20° C. whilethe stirring was continued for a further 4 hours. 5.5 g of4-iodo-3-fluoro-6-methoxyquinoline in solution in 100 cm³ oftetrahydrofuran were added, followed by 11.2 g of tribasic potassiumphosphate, and finally 386 mg of palladiumdiphenylphosphinoferrocenechloride. The reaction mixture was heated for 2 hours under reflux andthen stirred for 48 hours at room temperature. The suspension obtainedwas filtered. The filtrate was concentrated and then taken up in 200 cm³of ethyl acetate. The solution obtained was washed twice with 200 cm³ ofwater and then twice with 200 cm³ of a saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered and then concentratedunder reduced pressure (5 kPa) at a temperature in the region of 40° C.15 g of an oil were obtained, which oil was purified by chromatography,under a nitrogen pressure of 50 kPa, on a column of silica gel (particlesize 20-45 μ; diameter 6 cm; height 38 cm), eluting with acyclohexane-ethyl acetate mixture (85/15 by volume, making a gradient upto 70/30 by volume). 200-cm³ fractions were collected. Fractions 31 to34 were combined and then concentrated. 4.7 g of methyl(4RS)-1-benzyloxycarbonyl-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-ylidenacetate(Z isomer) were obtained in the form of a colorless oil.

[0240] Infrared spectrum (CCl₄): 3091; 3068; 3034; 1705; 1655; 1622;1507; 1468; 1434; 1361; 1263; 1231; 1207; 1173; 1141; 1034; 909; 832 and696 cm⁻¹

[0241] e) Methyl(4RS)-4-allyl-1-benzyloxycarbonylpiperidin-3-ylidenacetate, Z Isomer

[0242] A solution containing 16.3 g of(4RS)-4-allyl-1-benzyloxycarbonylpiperidin-3-one in 200 cm³ of toluenewas stirred under reflux with methyl(triphenylphosphoranylidene)acetate, under an inert atmosphere, for 16hours. After cooling to about 20° C., the reaction mixture wasconcentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C., the residue obtained, solubilized in 50 cm³ ofdichloromethane in the hot state, was purified by chromatography, undera nitrogen pressure of 50 kPa, on a column of silica gel (particle size20-45 μ; diameter 10 cm; height 45 cm), eluting with a cyclohexane-ethylacetate (80/20 by volume) mixture. 250-cm³ fractions were collected.Fractions 13 to 15 were combined and then concentrated as above. 5.8 gof methyl (4RS)-4-allyl-1-benzyloxycarbonylpiperidin-3-ylidenacetate (Zisomer) were obtained in the form of a colorless oil.

[0243] Infrared spectrum (CCl₄): 3068; 3034; 2949; 2853; 1722; 1705;1655; 1643; 1434; 1260; 1200; 1174; 1144; 993; 918 and 696 cm⁻¹

[0244] (4RS)-4-allyl-1-benzyloxycarbonylpiperidin-3-one may be preparedaccording to Takeuchi Y et al. described in Synthesis, 10:1814 (1999).

EXAMPLE 2

[0245] a)(3RS,4RS)₄-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-ylthio)ethyl]piperidine-3-aceticAcid Dihydrochloride

[0246] A solution of 70 mg of ethyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-ylthio)ethyl]piperidine-3-acetate,1 cm³ of dioxane and 0.3 cm³ of a 1 N aqueous sodium hydroxide solutionwas heated, with stirring, at a temperature in the region of 60° C. for1 hour. After concentrating the reaction mixture under reduced pressure(5 kPa) at a temperature in the region of 40° C., the residue obtainedwas taken up in 25 cm³ of water and 10 cm³ of dichloromethane. Theaqueous phase was separated after settling out and then acidified bypouring 0.3 cm³ of 1 N hydrochloric acid. The precipitate formed wasdissolved by adding 25 cm³ of dichloromethane. The organic phase waswashed with 10 cm³ of a saturated aqueous sodium chloride solution anddried over magnesium sulfate, filtered and concentrated under reducedpressure (5 kPa) at a temperature in the region of 40° C. The residueobtained was then dissolved in the hot state in 2 cm³ of acetone. 0.07cm³ of 4 N hydrochloric acid in dioxane were poured over this solution.The resulting mixture was concentrated under reduced pressure (5 kPa) ata temperature in the region of 40° C. 72 mg of(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-ylthio)ethyl]piperidine-3-aceticacid dihydrochloride were obtained in the form of a powder, which waswhite in color.

[0247]¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 with a few drops of CD3COODd4 at a temperature of 373K, δ in ppm): from 1.20 to 2.00 (mt: 7H); from2.00 to 2.60 (mt: 5H); from 2.75 to 3.20 (mt: 6H); 3.94 (s: 3H); 4.89(broad t, J=7 Hz: 1H); 7.07 (mt: 1H); 7.24 (mt: 1H); 7.37 (dd, J=9 and2.5 Hz: 1H); 7.60 (broad d, J=5 Hz: 1H); from 7.90 to 8.00 (mt: 2H);8.62 (broad s: 1H).

[0248] b) Methyl(3RS,4RS)₄-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate

[0249] A solution composed of 0.92 g of methyl (3RS,4RS) and(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetatedihydrochloride, 0.85 cm³ of triethylamine, 535 mg of2-(2-bromoethylthio)thiophene in 30 cm³ of anhydrous dimethylformamidewas stirred for 4 hours 30 minutes at a temperature in the region of 60°C. under an inert atmosphere. 0.3 cm³ of triethylamine were then addedand the mixture was again heated at 60° C. under an inert atmosphere for15 hours. After cooling to about 20° C., the reaction mixture was pouredover 100 cm³ of water and 100 cm³ of ethyl acetate. The organic phasewas separated after settling out, washed 4 times with 15 cm³ of waterand then twice with 50 cm³ of a saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered and concentrated underreduced pressure (5 kPa) at a temperature in the region of 40° C. Theresidue obtained was purified by chromatography, under a nitrogenpressure of 50 kPa, on a column of silica gel (particle size 20-45 μ;diameter 1 cm; height 40 cm), eluting with a cyclohexane-ethyl acetate(50/50 by volume) mixture. 20-cm³ fractions were collected. Fractions 13to 15 were concentrated. 70 mg of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetatewere obtained in the form of an oil, which was yellow in color.

[0250] Infrared spectrum (CCl₄): 3617; 2934; 2799; 2764; 1737; 1623;1508; 1467; 1231; 1033; 101 1; 834 and 698 cm¹

[0251] c) Methyl (3RS,4RS) and(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetateDihydrochloride

[0252] A solution of 940 mg of (3RS,4RS) and(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-aceticacid in 20 cm³ of methanol was cooled to a temperature in the region of−25° C., with stirring and under an inert atmosphere. 0.43 cm³ ofthionyl chloride were added to this solution over 5 minutes. The mixturewas brought to a temperature in the region of 20° C. while the stirringwas continued for a further 1 hour 30 minutes. The reaction mixture wasconcentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. and then 30 cm³ of methanol were added. This series ofoperations was repeated 3 times. 920 mg of methyl (3RS,4RS) and(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetatedihydrochloride were obtained in the form of a yellow foam.

[0253] Infrared spectrum (KBr): 3249; 1949; 2503; 2020; 1731; 1622;1604; 1555; 1497; 1457; 1420; 1308; 1242; 1200; 1175; 1080; 1014; 872;832 and 795 cm⁻¹

[0254] d) (3RS,4RS) and(3SR,4RS)₄-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-aceticAcid

[0255] A solution of 1.16 g of methyl (3RS,4RS) and(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)₃-propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetate,100 cm³ of anhydrous dimethyl sulfoxide and 25 cm³ of anhydroustert-butanol was stirred under an inert atmosphere free of water at 20°C. This colorless solution was purged with pure oxygen until thereaction mixture became saturated. A solution containing 685 mg ofpotassium tert-butoxide in 8 cm³ of anhydrous tert-butanol was thenadded. Oxygen was again introduced by bubbling for a further 3 hours and30 minutes with vigorous stirring. The yellow solution obtained waspurged with nitrogen and then cooled to 0° C. 0.5 cm³ of pure aceticacid in 20 cm³ of water were then added followed by 200 cm³ of ether.The organic phase was separated after settling out, washed 7 times with20 cm³ of water and 3 times with 20 cm³ of a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered andconcentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. A gum was obtained, which was taken up in 20 cm³ ofether. The medium was again concentrated under the same conditions asabove. 945 mg of (3RS,4RS) and(3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-aceticacid were obtained in the form of a white foam.

[0256] Infrared spectrum (KBr): 2973; 2932; 2864; 1693; 1668; 1623;1510; 1468; 1429; 1366; 1232; 1166; 1030 and 831 cm⁻¹

[0257] Infrared spectrum (CH₂Cl₂): 3600; 2982; 2939; 2867; 1710; 1682;1623; 1509; 1468; 1429; 1367; 1231; 1162; 1030; 909; 896 and 834 cm⁻¹

[0258] e) Methyl (3RS,4RS) and(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetate

[0259] A solution of 1.85 g of methyl (3RS,4RS) and(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate,0.7 cm³ of triethylamine and 40 cm³ of dichloromethane was cooled, to atemperature in the region of 0° C., with stirring and under an argonatmosphere. A solution of 1.16 g of di-tert-butyldicarbonate dissolvedin 40 cm³ of dichloromethane was added to this colorless solution over20 minutes. The mixture was brought to a temperature in the region of20° C. while the stirring was continued for a further 10 hours. 200 cm³of water were then added to the reaction mixture. The organic phase wasseparated after settling out, washed with 100 cm³ of a saturated aqueoussodium chloride solution, dried over magnesium sulfate, filtered andthen concentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. An oil was obtained, which was purified bychromatography, under a nitrogen pressure of 50 kPa, on a column ofsilica gel (particle size 20-45 μ; diameter 2 cm; height 20 cm), elutingwith a cyclohexane-ethyl acetate (70/30 by volume) mixture. 40-cm³fractions were collected. Fractions 8 to 12 were combined and thenconcentrated as above. 2.16 g of methyl (3RS,4RS) and(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetatewere obtained in the form of a colorless oil.

[0260] Infrared spectrum (CCl₄) 3006; 1740; 1695; 1622; 1507; 1468;1428; 1366; 1231; 1166; 1034; 909 and 832 cm⁻¹

EXAMPLE 3

[0261] a) (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetic AcidHydrochloride

[0262] A solution of 195 mg of methyl(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate,2 cm³ of dioxane and 0.9 cm³ of a 1 N aqueous sodium hydroxide solutionwas heated, with stirring, at a temperature in the region of 60° C. for1 hour. After concentrating the reaction mixture under reduced pressure(5 kPa) at a temperature in the region of 40° C., the residue obtainedwas taken up in 20 cm³ of water and 10 cm³ of ether. The aqueous phasewas separated after settling out and then acidified by adding 0.9 cm³ of1 N hydrochloric acid. The precipitate formed was dissolved with 20 cm³of dichloromethane. The organic phase was washed twice with 10 cm³ of asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered, concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. The product obtained was thenstirred in 20 cm³ of acetone. A solution of 2 cm³ of 4 N hydrochloricacid in dioxane was poured over this solution. The reaction mixture wasconcentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. and then 5 cm³ of acetone were added. This operationwas repeated 4 times. 155 mg of(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-aceticacid hydrochloride were obtained in the form of a solid which wasoff-white in color.

[0263]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.15 to2.10 (mt: 8H); 2.10 (dd, J=15 and 7.5 Hz: 1H); 2.47 (dd, J=15 and 4 Hz:1H); from 2.70 to 2.95 (mt: 2H); 3.07 (broad t, J=7 Hz: 2H); 3.20 (mt:4H); 3.44 (mt: 2H); 3.96 (s: 3H); 7.11 (dd, J=5.5 and 4 Hz: 1H); 7.32(dd, J=4 and 1.5 Hz: 1H); 7.40 (mt: 1H); 7.41 (dd, J=9 and 2.5 Hz: 1H);7.72 (dd, J=5.5 and 1.5 Hz: 1H); 7.97 (d, J=9 Hz: 1H); 8.71 (broad s:1H); from 9.85 to 10.05 (unresolved complex: 1H).

[0264] b) Methyl(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate

[0265] A solution composed of 0.95 g of methyl (3RS,4RS) and(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate,0.7 g of potassium carbonate, 0.68 g of 2-(2-bromoethylthio)thiophene in40 cm³ of dimethylformamide was stirred for 16 hours at a temperature inthe region of 60° C. under an inert atmosphere. After cooling to about20° C., the reaction mixture was supplemented with 200 cm³ of water and200 cm³ of ethyl acetate. The organic phase was separated after settlingout and then washed 5 times with 100 cm³ of water and then with 100 cm³of a saturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. The evaporation residue obtained waspurified by chromatography, under a nitrogen pressure of 50 kPa, on acolumn of silica gel (particle size 20-45 μ; diameter 2 cm; height 40cm), eluting with a cyclohexane-ethyl acetate (68/32 by volume) mixture.15-cm³ fractions were collected. Fractions 33 to 36 were concentrated.195 mg of methyl(3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetatewere obtained in the form of an orange-colored oil.

[0266]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.00 to1.80 (mt: 9H); 1.89 (very broad t, J=10.5 Hz: 1H); 2.07 (dd, J=15 and7.5 Hz: 1H); from 2.35 to 2.55 (mt: 3H); from 2.65 to 2.80 (mt: 2H);2.90 (t, J=7 Hz: 2H); 3.05 (broad t, J=6.5 Hz: 2H); 3.56 (s: 3H); 3.95(s: 3H); 7.04 (dd, J=5 and 3.5 Hz: 1H); 7.17 (dd, J=3.5 and 1.5 Hz: 1H);7.37 (mt: 1H); 7.40 (dd, J=9 and 2.5 Hz: 1H); 7.60 (dd, J=5 and 1.5 Hz:1H); 7.96 (d, J=9 Hz: 1H); 8.69 (broad s: 1H).

EXAMPLE 4

[0267] a)(3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-aceticacid

[0268] A mixture of 0.355 g of methyl(3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetatein 1.66-cm³ of a 1 N aqueous sodium hydroxide solution and 5-cm ofdioxane was heated at a temperature in the region of 60° C., withstirring, for 2 hours. After cooling to about 20° C., the reactionmixture was concentrated to dryness under reduced pressure (2 kPa) at atemperature in the region of 50° C. The evaporation residue obtained wastaken up in 30-cm³ of water and 30-cm³ of diethyl ether, the aqueousphase was separated after settling out and neutralized with 1.66-cm³ ofa 1 N aqueous hydrochloric acid solution and was then extracted twicewith 100-cm³ of ethyl acetate. The organic phase was dried overmagnesium sulfate, filtered and then concentrated to dryness accordingto the same conditions above. 0.238 g of(3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-aceticacid were obtained in the form of a white solid.

[0269]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 0.95 to2.80 (mts: 16H); 2.87 (mt: 2H); 3.93 (s: 3H); 4.65 (broad t, J=7 Hz:1H); 7.04 (broad dd, J=5.5 and 3.5 Hz: 1H); 7.16 (broad d, J=3.5 Hz:1H); 7.37 (very broad d, J=9.5 Hz: 1H); 7.60 (broad d, J=5.5 Hz: 1H);7.85 (mt: 1 H); 7.94 (d, J=9.5 Hz: 1 H); 8.66 (mt: 1 H).

[0270] b) Methyl(3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate

[0271] 0.695 g of sodium borohydride was added in several portions to amixture of 0.98 g of methyl(3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetatein 50-cm³ of methanol cooled to the region of −5° C., with stirring andunder inert atmosphere. The reaction was very exothermic and in thevicinity of 0° C., 0.365 g of molybdenum trioxide were added all atonce. The reaction mixture was stirred in the region of 20° C. for 20hours and then it was cooled to the vicinity of −6° C. and 0.695 g ofsodium borohydride and 0.365 g of molybdenum trioxide were again added.The reaction mixture was stirred for 5 hours in the region of 20° C. andwas then filtered on celite and the insoluble matter was washed twicewith 50-cm³ of methanol. The filtrate was concentrated to dryness underreduced pressure (2 kPa) at a temperature in the region of 40° C. Theevaporation residue was purified by chromatography under an argonpressure of 50 kPa, on a column of silica gel (particle size 40-60 m;diameter 3 cm; height 25 cm), eluting with a successive mixture ofcyclohexane-ethyl acetate (50/50 by volume), ethyl acetate and thendichloromethane-methanol (90/10 by volume) and collecting 50-cm³fractions. Fractions 17 to 20 were combined and then concentrated todryness according to the conditions described above. 0.355 g of methyl(3RS,4RS)-4-[3-(R,S)amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetatewere obtained in the form of a colorless oil.

[0272] Infrared spectrum: (CCl₄) 2932; 2765; 1736; 1623; 1508; 1230;1167; 1033; 833 and 699 cm⁻¹

[0273] c) Methyl(3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate

[0274] 0.363 g of hydroxylamine hydrochloride was added in severalportions to a mixture of 0.99 g of methyl(3RS,RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2-thienylthio)ethyl]piperidine-3-acetatein 10-cm³ of pyridine, with stirring and under an inert atmosphere, andthe resulting mixture was heated in the region of 60° C. for 16 hours.After cooling in the region of 20° C., the reaction mixture wasconcentrated to dryness under reduced pressure (8 kPa) at a temperaturein the region of 55° C. The evaporation residue was taken up in 75-cm³of ethyl acetate and 40-cm³ of distilled water. The organic phase waswashed three times with 40-cm³ of distilled water and 40-cm³ of asaturated sodium chloride solution, dried over magnesium sulfate for 30minutes, filtered and concentrated to dryness under reduced pressure (2kPa) at a temperature in the region of 40° C. 0.98 g of methyl(3RS,4RS)-4-[3-hydroxyimino-3-(fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2-thienylthio)ethyl]piperidine-3-acetatewereobtained in the form of a yellow gum.

[0275] Mass spectrum: El m/z=528 [M—OH]⁺

[0276] m/z=514 [M—OCH₃]⁺

[0277] m/z=416 [M—C₅H₅S₂]⁺ base peak

[0278] m/z=115 [C₄H₃S₂]⁺

[0279] DCI m/z=546 MH⁺

[0280] d) Methyl(3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate

[0281] 4.7-cm³ of dimethyl sulfoxide in 15-cm³ of dichloromethane werepoured, over 10 minutes, into a solution of 3.3-cm³ of oxalyl dichloridein 40 m³ of dichloromethane cooled to −70° C., with stirring and underan inert atmosphere. After 10 minutes, a solution of 4 g of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetatein 25-cm³ of dichloromethane was poured in over 10 minutes. After 20minutes, in the region of −70° C., 21-cm³ of triethylamine in 20-cm³ ofdichloromethane were added dropwise over 15 minutes and the reactionmixture was stirred for 15 minutes in the region of −70° C. and then for2 hours in the region of 20° C. 100-cm³ of distilled water were pouredover the reaction mixture, the organic phase was separated aftersettling out, washed with 100-cm³ of a saturated aqueous sodium hydrogencarbonate solution, twice with 75-cm³ of water and 75-cm³ of a saturatedaqueous sodium chloride solution. The organic extract was dried overmagnesium sulfate for 30 minutes, filtered and concentated to drynessunder reduced pressure (2 kPa) at a temperature in the region of 40° C.The residue obtained was purified by chromatography under an argonpressure of 50 kPa, on a column of silica gel (particle size 40-60 μ;diameter 3 cm; height 40 cm), eluting with a cyclohexane-ethyl acetate(60/40 by volume) mixture and collecting 50-cm³ fractions. Fractions 11to 16 were combined and then concentrated to dryness according to theconditions described above. 3.16 g of methyl(3RS,4RS)-4-[3-oxo-3-(fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2-thienylthio)ethyl]piperidine-3-acetatewere obtained in the form of a yellow oil.

[0282] Infrared spectrum: (CCl₄): 2930; 1738; 1699; 1621; 1505; 1231;1198; 1154; 1028; 834; 699 cm⁻¹.

EXAMPLE 5

[0283] a)(3RS,4RS)₄-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2,5-difluorophenylthio)ethyl]piperidine-3-aceticAcid Hydrochloride

[0284] A mixture of 0.2 g of methyl(3RS,4RS)₄-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2,5-difluorophenylthio)ethyl]piperidine-3-acetatein 3-cm³ of methanol, 3-cm³ of dioxane and 1.77-cm³ of a 10 N aqueoussodium hydroxide solution was heated at a temperature in the region of65° C., with stirring, for 22 hours. After cooling in the vicinity of20° C., the reaction mixture was concentrated to dryness under reducedpressure (2 kPa) at a temperature in the region of 50° C. Theevaporation residue obtained was taken up in 10-cm³ of distilled waterand acidified with a sufficient volume of a concentrated acetic acidsolution in order to obtain a pH in the region of 5-6. The mixture wasextracted with 20-cm³ of ethyl acetate, the organic phase was dried overmagnesium sulfate, filtered and concentrated to dryness according to theconditions described above. The oil obtained was taken up in 10-cm³ ofacetone and 10-cm³ of a hydrochloric dioxane solution and thenconcentrated to dryness under reduced pressure (2 kPa) at a temperaturein the region of 40° C. The residue was again taken up in 10-cm³ ofacetone and then concentrated to dryness under reduced pressure (2 kPa)at a temperature in the region of 40° C. and then dried in a desiccatorfor 18 hours. 0.181 g of(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2,5-difluorophenylthio)ethyl]piperidine-3-aceticacid hydrochloride were obtained in the form of an orange-colored pourersolid melting in the vicinity of 124° C.

[0285]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm). A mixture of twostereoisomers in approximate proportions 60/40 was observed.

[0286] * from 1.00 to 3.85 (mts: 18H); 3.89 and 4.07 (2 broad s: 3H intotal); 5.34 and 5.49 (2 mts: 1H in total); from 7.05 to 7.55 (mts: 4H);from 7.90 to 8.20 (mt: 2H); 8.68 and 8.85 (2 broad s: 1H in total); from9.65 to 10.70 (unresolved complex: 2H in total).

[0287] b) Methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate

[0288] A mixture of 6.5 g of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetatedihydrochloride, 3.9 g of 2-(2-bromoethylthio)-1,4-difluorobenzenedissolved in 10-cm³ of dimethylformamide, 2.32 g of potassium iodide,5.8 g of potassium carbonate and 3.93-cm³ of trietylamine in 200-cm³ ofacetonitrile was heated with stirring and under an inert atmosphere, for22 hours at a temperature in the region of 70° C. After cooling to atemperature in the region of 20° C., the reaction mixture was filteredand the insoluble matter was washed twice with 30-cm³ of acetonitrile.The filtrate was concentrated to dryness under reduced pressure (2 kPa)at a temperature in the region of 40° C. The evaporation residue wastaken up in 100-cm³ of distilled water and 150-cm³ of ethyl acetate. Theorganic phase was washed 3 times with 100-cm³ of distilled water andtwice with 100-cm³ of a saturated aqueous sodium chloride solution,dried over magnesium sulfate and concentrated to dryness according tothe conditions described above. The oil obtained was purified bychromatography under an argon pressure of 50 kPa, on a column of silicagel (particle size 40-60 μm; diameter 4 cm), eluting with acyclohexane-ethyl acetate (50/50 by volume) mixture and collecting60-cm³ fractions. The fractions containing the expected product werecombined and then concentrated to dryness under reduced pressure (2 kPa)at a temperature in the region of 40° C. 1.7 g of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetatewere obtained in the form of an orange-colored pourer viscous oil.

[0289]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm). The mixture oftwo stereoisomers in the proportions 50/50 was observed.

[0290] * from 0.90 to 2.60 (mt: 14H); from 2.60 to 2.80 (mt: 2H); 3.08(broad t, J=7 Hz: 2H); 3.47 and 3.55 (2 s: 3H in total); 3.89 (s: 3H);5.33 (very broad t, J=7 Hz: 1H); 5.83 (broad s: 1H); 7.05 (mt: 1H); from7.15 to 7.35 (mt: 2H); 7.38 (d mt, J=9 Hz: 1H); from 7.90 to 8.00 (mt:2H); 8.68 (broad s: 1H).

EXAMPLE 6

[0291] a)(3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-aceticAcid Hydrochloride

[0292] A mixture of 0.09 g of methyl(3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetatein 0.36-cm³ of a 1 N aqueous sodium hydroxide solution and 3-cm³ ofdioxane was heated at a temperature in the region of 55° C., withstirring and under an inert atmosphere, for 4 hours. After cooling inthe vicinity of 20° C., the reaction mixture was concentrated to drynessunder reduced pressure (2 kPa) at a temperature in the region of 50° C.The evaporation residue obtained was taken up in 5-cm³ of distilledwater and acidified with a 1-N aqueous hydrochloric acid solution andwas concentrated. The aqueous phase was washed with 8-cm³ ofdichloromethane and then concentrated according to the conditionsdescribed above. The residue obtained was taken up in 10-cm³ of acetoneand then it was filtered on sintered glass. 0.081 g of(3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-aceticacid hydrochloride wereobtained in the form of a white solid.

[0293] NMR spectrum ¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 with additionof a few drops of CD₃COOD d4, at a temperature of 383K, δ in ppm). Amixture of stereoisomers was observed.

[0294] * from 1.20 to 2.55 (mt: 12H); from 2.80 to 3.60 (mt: 6H); 4.03(s: 3H); 5.16 (mt: 1H); 7.12 (mt: 1H); 7.25 (mt: 1H); 7.42 (mt: 1H);7.49 (broad d, J=9 Hz: 1H); 7.54 (mt: 1H); 8.06 (d, J=9 Hz: 1H); 8.76(broad s: 1H).

[0295] b) Methyl(3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate

[0296] 0.261 g of sodium borohydride was added, in several portions, toa mixture of 0.4 g of methyl(3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetatein 25-cm³ of methanol cooled in the region of −2° C., with stirring andunder an inert atmosphere. The reaction mixture was stirred in theregion of 0° C. for 20 minutes and then 0.14 g of molybdenum trioxidewereadded. The reaction mixture was stirred in the region of 20° C. for24 hours and then it was cooled in the vicinity of −2° C. and 0.261 g ofsodium borohydride and 0.14 g of molybdenum trioxide were again added.The reaction mixture was stirred for 18 hours in the region of 20° C.and then filtered on celite. The filtrate was concentrated to drynessunder reduced pressure (2 kPa) at a temperature in the region of 40° C.The evaporation residue was purified by chromatography under an argonpressure of 50 kPa, on a column of silica gel (particle size 40-60 μm;diameter 3 cm), eluting with a successive mixture of cyclohexane-ethylacetate (50/50 by volume) and then dichloromethane-methanol (90/10 byvolume) and collecting 10-cm³ fractions. Fractions 26 to 41 werecombined and then concentrated to dryness according to the conditionsdescribed above. 0.202 g of methyl(3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetatewere obtained in the form of a colorless oil.

[0297] Infrared spectrum: (CCl₄)

[0298] 2938; 1736; 1623; 1507; 1484; 1230; 1189; 1168; 1033; 909 and 833cm⁻¹

[0299] c) Methyl(3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate

[0300] 0.347 g of hydroxylamine hydrochloride wereadded, in severalportions, to a mixture of 1 g of methyl(3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)—1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetatein 10-cm³ of pyridine, with stirring and under an inert atmosphere, andthe resulting mixture was stirred in the region of 20° C. for 24 hoursand then for 20 hours in the region of 50° C. and for 1.25 hours in theregion of 62° C. After cooling in the region of 20° C., the reactionmixture was concentrated to dryness under reduced pressure (1.5 kPa) ata temperature in the region of 50° C. The evaporation residue was takenup in 70-cm³ of ethyl acetate and 40-cm³ of distilled water. The organicphase was separated after settling out, washed 3 times with 40-cm³ ofdistilled water and 40-cm³ of a saturated sodium chloride solution,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2 kPa) at a temperature in the region of 40° C. Theevaporation residue was purified by chromatrography under an argonpressure of 50 kPa, on a column of silica gel (particle size 40-60 μm;diameter 3 cm), eluting with a successive mixture of cyclohexane-ethylacetate (60/40 by volume) and then dichloromethane-methanol (90/10 byvolume) and collecting 10-cm³ fractions. Fractions 1 to 21 were combinedand then concentrated to dryness according to the conditions describedabove. 0.813 g of methyl(3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetatewereobtained in the form of a whitish viscous oil.

[0301] Infrared spectrum: (CCl₄)

[0302] 3585; 3174; 2930; 1738; 1621; 1506; 1484; 1229; 1189; 1167; 1029;909 and 833 cm⁻¹

[0303] d) Methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin4-yl)propyl)-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate

[0304] 1.88-cm³ of dimethyl sulfoxide in 6-cm³ of dichloromethane werepoured, over 10 minutes, into a solution of 1.32-cm³ of oxalyldichloride in 30-cm³ of dichloromethane cooled to −70° C., with stirringand under an inert atmosphere. After 10 minutes, a solution of 1.7 g ofmethyl(3RS,4RS)₄-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetatein 15-cm³ of dichloromethane was poured in over 10 minutes. After 15minutes, 8.4-cm³ of triethylamine in 10-cm³ of dichloromethane wereadded dropwise over 15 minutes and the reaction mixture was stirred for45 minutes in the region of −70° C. and then for 20 hours in the regionof 20° C. 50-cm³ of distilled water were poured over the reactionmixture, the organic phase was separated after settling out, washed with50-cm³ of a saturated aqueous sodium hydrogen carbonate solution, twicewith 30-cm³ of distilled water and 30-cm³ of a saturated aqueous sodiumchloride solution. The organic extract was dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure (2 kPa) at atemperature in the region of 40° C. The residue obtained was purified bychromatography under an argon pressure of 50 kPa, on a column of silicagel (particule size 40-60 μm; diameter 3-cm), eluting with acyclohexane-ethyl acetate (60/40 by volume) mixture and collecting10-cm³ fractions. The fractions containing the expected product werecombined and then concentrated to dryness according to the conditionsdescribed above. 1.37 g of methyl(3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetatewere obtained.

[0305] Infrared spectrum: (CCl₄) 2930; 1737; 1701; 1621; 1506; 1484;1468; 1232; 1189; 1166; 1028; 905 and 834 cm⁻¹

EXAMPLE 7

[0306] a)(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2,5-cyclopentanethio)ethylpiperidine-3-aceticAcid Hydrochloride

[0307] A mixture of 0.12 g of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2,5-cyclopentanethio)-ethyl-piperidine-3-acetatein 2-cm³ of dioxane and 0.6-cm³ of a 1 N aqueous sodium hydroxidesolution was heated at a temperature in the region of 55° C., withstirring, for 18 hours. After cooling in the vicinity of 20° C., thereaction mixture was concentrated to dryness under reduced pressure (2kPa) at a temperature in the region of 50° C. The evaporation residuewas taken up in 5-cm³ of distilled water, acidified with a sufficientvolume of a 1 N aqueous hydrochloric acid solution in order to obtain apH in the region of 6. The mixture was extracted with 8-cm³ ofdichloromethane and the organic phase was dried over magnesium sulfate,filtered and concentrated to dryness according to the same conditionsdescribed above. The residue was taken up in 5-cm³ of acetone and 1-cm³of a 4 N hydrochloric acid solution in dioxane and then concentrated todryness under reduced pressure (1 kPa) at a temperature in the region of50° C. The residue was again taken up in 5-cm³ of acetone andconcentrated to dryness according to the conditions described above.0.078 g of(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2,5-cyclopentanethio)ethyl]piperidine-3-aceticacid hydrochloride wereobtained in the form of an orange-colored pourerpowder melting in the vinicinity of 125° C.

[0308] NMR spectrum ¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 with additionof a few drops of CD₃COOD d4, at a temperature of 383K, δ in ppm): from1.20 to 2.55 (mt: 18H); 2.89 (mt: 2H); from 3.00 to 3.35 (mt: 7H); 3.94(s: 3H); 5.39 (mt: 1H); 7.39 (dd, J=9 and 2 Hz: 1H); 7.97 (d, J=9 Hz:1H); 7.99 (mt: 1H); 8.63 (broad s: 1H).

[0309] b) Methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2,5-cyclopentanethio)ethylpiperidine-3-acetate

[0310] A mixture of 1 g of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-piperidine-3-acetatehydrochloride, 0.424 g of (2-chloroethylthio)cyclopentane, 0.388 g ofpotassium iodide, 0.97 g of potassium carbonate and 0.656-cm³ oftrietylamine in 30-cm³ of acetonitrile was heated, with stirring, for 18hours at a temperature in the region of 65° C. After cooling to atemperature in the region of 20° C., the reaction mixture was filteredand the insoluble matter was washed twice with 20-cm³ of acetonitrile.The filtrate was concentrated to dryness under reduced temperature (1kPa) at a temperature in the region of 50° C. The evaporation residuewas taken up in 20-cm³ of distilled water and 30-cm³ of ethyl acetate.The organic phase was washed twice with 20-cm³ of distilled water andtwice with 20-cm³ of a saturated aqueous sodium chloride solution, driedover magnesium sulfate, filtered and concentrated to dryness accordingto the conditions described above. The oil obtained was purified bychromatography under an argon pressure of 50 kPa, on a column of silicagel (particle size 40-60 μm; diameter 3 cm), eluting with a successivemixture of cyclohexane-ethyl acetate (60/40 by volume) and thendichloromethane-methanol (90/10 by volume) and collected 6-cm³fractions. Fractions 6 to 25 were combined and then concentrated todryness under reduced pressure (2 kPa) at a temperature in the region of40° C. 0.42 g of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentanethio)ethyl]piperidine-3-acetatewere obtained in the form of a yellow oil.

[0311] Infrared spectrum: (CCl₄)

[0312] 3616; 2928; 2853; 1737; 1623; 1508; 1231; 1165; 1032; 907 and 834cm¹

[0313] The preparation of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)]propylpiperidine-3-acetatehydrochloride was described above.

EXAMPLE 8

[0314] a) Synthesis of stereoisomers of4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-aceticAcid

[0315] The absolute stereochemistry of each stereoisomer calledhereinafter I, II, III, IV, V, VI, VII is not known.

[0316] Stereoisomer I

[0317] A solution of 0.625 9 of methyl4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-(thienylthio)ethyl)]piperidine-3-acetate(stereoisomer 1) in 10-cm³ of dioxane and 3-cm³ of a 1 N aqueous sodiumhydroxide solution was heated, with stirring, at a temperature in theregion of 60° C. for 1 hour. After concentrating the reaction mixtureunder reduced pressure (5 kPa) at a temperature in the region of 40° C.,the residue obtained was taken up in 10-cm³ of water, acidified with a 1N aqueous hydrochloric acid solution. The precipitate formed wasfiltered, dried in an oven under a reduced pressure (10 Pa) at atemperature in the region of 20° C. for 18 hours. The product obtainedwas then stirred in 30-cm³ of acetone; a 4 N hydrochloric acid solutionin dioxane was then poured in. The reaction mixture was concentratedunder reduced pressure (5 kPa) at a temperature in the region of 40° C.and then the product was taken up with acetone 3 times by evaporatingaccording to the conditions described above, at each stage. 0.42 g of4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-aceticacid dihydrochloride (stereoisomer 1) were obtained in the form of awhite solid. (αD²⁰=+56.9° +/−1.0 in methanol at 0.5%).

[0318]¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 with addition of a few dropsof CD₃COOD d4, at a temperature of 373K, δ in ppm): from 1.25 to 2.65(mt: 9H); 2.33 (dd, J=15 and 5 Hz: 1H); from 3.05 to 3.40 (mt: 8H); 3.94(s: 3H); 5.40 (broad t, J=7 Hz: 1H); 7.09 (mt: 1H); 7.28 (broad d, J=3Hz: 1H); 7.37 (very broad d, J=9 Hz: 1H); 7.62 (broad d, J=5 Hz: 1H);from 7.90 to 8.00 (mt: 2H); 8.61 (broad s: 1H).

[0319] Stereoisomer II

[0320] A solution of 0.545 g methyl4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-(thienylthio)ethyl)]piperidine-3-acetate(stereoisomer II) in 10-cm³ of dioxane and 2.6-cm³ of a 1 N aqueoussodium hydroxide solution was heated, with stirring, at a temperature inthe region of 60° C., for 1 hour. After concentrating the reactionmixture under reduced pressure (5 kPa) at a temperature in the region of40° C., the residue obtained was taken up in 10-cm³ of water, acidifiedwith a 1 N aqueous hydrochloric acid solution in order to obtain a pHequal to 6. The suspension was taken up in 20-cm³ of dichloromethane andthen the organic phase was separated after settling out, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure (5kPa) at a temperature in the region of 40° C. The product obtained wasthen stirred in 20-cm³ of acetone and a 4 N hydrochloric acid solutionwas poured into dioxane. The precipitate formed was filtered, dried inan oven under reduced pressure (10 Pa) at a temperature in the region of20° C. for 18 hours. The residue obtained was then taken up in acetoneseveral times while evaporating according to the conditions describedabove, at each stage. 0.43 g of4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-aceticacid dihydrochloride (stereoisomer II) were obtained in the form of awhite solid. (αD²⁰=+55.9° +/−0.9 in methanol at 0.5%).

[0321]¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 with addition of a few dropsof CD₃COOD d4, at a temperature of 373K, δ in ppm): from 1.25 to 2.60(mt: 10H); from 3.00 to 3.40 (mt: 8H); 3.94 (s: 3H); 5.39 (dd, J=7 and 5Hz: 1H); 7.09 (dd, J=5 and 3 Hz: 1H); 7.28 (broad d, J=3 Hz: 1H); 7.38(dd, J=9 and 2.5 Hz: 1H); 7.63 (broad d, J=5 Hz: 1H); from 7.90 to 8.05(mt: 2H); 8.63 (broad s: 1H).

[0322] Stereoisomer III

[0323] A solution of 0.458 g of methyl4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-(thienylthio)ethyl)]piperidine-3-acetate(stereoisomer II) in 10-cm³ of dioxane and 2.2-cm³ of a 1 N aqueoussodium hydroxide solution was heated, with stirring at a temperature inthe region of 60° C., for 1 hour. After concentrating the reactionmixture under reduced pressure (5 kPa) at a temperature in the region of40° C., the residue obtained was taken up in 10-cm³ of water, acidifiedwith an aqueous acetic acid solution in order to obtain a pH equal to 6.The suspension was taken up in 20-cm³ of dichloromethane and then theorganic phase was separated after settling out, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. The product obtained was thenstirred in 20-cm³ of acetone; a 4 N hydrochloric acid solution indioxane was then poured in. The precipitate formed was filtered, driedin an oven under reduced pressure (10 Pa) at a temperature in the regionof 20° C. for 18 hours. The residue obtained was then taken up inacetone several times while evaporating according to the conditionsdescribed above at each stage. 0.42 g of4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-aceticacid (stereoisomer II) in the form of a white solid were obtained.(αD²⁰=−46.9° +/−0.9 in methanol at 0.5%).

[0324]¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 with addition of a few dropsof CD₃COOD d4, at a temperature of 373K, δ in ppm): from 1.25 to 2.60(mt: 10H); from 3.00 to 3.40 (mt: 8H); 3.94 (s: 3H); 5.39 (broad t, J=7Hz: 1H); 7.09 (mt: 1H); 7.28 (broad d, J=3 Hz: 1H); 7.38 (very broad d,J=9 Hz: 1H); 7.63 (broad d, J=5 Hz: 1H); from 7.90 to 8.05 (mt: 2H);8.62 (broad s: 1H).

[0325] Stereoisomer IV

[0326] A solution of 0.454 g of methyl4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-(thienylthio)ethyl)]piperidine-3-acetate(stereoisomer IV) in 10-cm³ of dioxane and 2.2-cm³ of a 1 N aqueoussodium hydroxide solution was heated with stirring at a temperature inthe region of 60° C., for 1 hour. After concentrating the reactionmixture under reduced pressure (5 kPa) at a temperature in the region of40° C., the residue obtained was taken up in 10-cm³ of water, acidifiedwith an aqueous acetic acid solution in order to obtain a pH equal to 6.The suspension was taken up in 20-cm³ of dichloromethane and then theorganic phase was separated after settling out, dried over magnesiumsulfate, filtered, concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. The product obtained was thenstirred in 20-cm³ of acetone and a 4 N hydrochloric acid solution indioxane was poured in. The precipitate formed was filtered, and dried inan oven under a reduced pressure (10 Pa) at a temperature in the regionof 20° C. for 18 hours. The residue obtained was then taken up inacetone several times while evaporating according to the conditionsdescribed above, at each stage. 0.35 g of4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-aceticacid dihydrochloride (stereoisomer IV) were obtained in the form of awhite solid. (αD²⁰=−54.8° +/−1.1 in methanol at 0.5%).

[0327]¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 with addition of a few dropsof CD₃COOD d4, at a temperature of 373K, δ in ppm): from 1.25 to 2.60(mt: 9H); 2.22 (broad dd, J=15 and 5 Hz: 1H); from 3.00 to 3.40 (mt:8H); 3.94 (s: 3H); 5.40 (mt: 1H); 7.10 (mt: 1H); 7.29 (broad d, J=3 Hz:1H); 7.38 (very broad d, J=9 Hz: 1H); 7.64 (broad d, J=5 Hz: 1H); from7.90 to 8.05 (mt: 2H); 8.62 (broad s: 1H).

[0328] Stereoisomer V

[0329] A solution of 0.560 g of methyl4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-(thienylthio)ethyl)]piperidine-3-acetate(stereoisomer V) in 10-cm³ of dioxane and 2.2-cm³ of a 1 N aqueoussodium hydroxide solution was heated with stirring at a temperature inthe region of 60° C., for 2 hours. After concentrating the reactionmixture under reduced pressure (5 kPa) at a temperature in the region of40° C., the residue obtained was taken up in 10-cm³ of water, acidifiedwith an aqueous acetic acid solution in order to obtain a pH equal to 6.The suspension was taken up in 20-cm³ of dichloromethane and then theorganic phase was separated after settling out, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. The product obtained was thenstirred in 20-cm³ of acetone; a 4 N hydrochloric acid solution indioxane was then poured in. The precipitate formed was concentratedunder reduced pressure (5 kPa) at a temperature in the region of 40° C.The residue obtained was then taken up in acetone several times whileevaporating according to the conditions described above at each stage,and then dried in an oven under a reduced pressure (10 Pa) at atemperature in the region of 20° C. for 120 hours. 0.4 g of4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-aceticacid were obtained (stereoisomer V) in the form of a white solid.(αD²⁰=+83.4° +/−1.3 in methanol at 0.5%).

[0330]¹H NMR spectrum (400 MHz, (CD₃)₂SO d6, δ in ppm): 0.95 (mt: 1H);1.41 (mt: 2H); from 1.65 to 2.15 (mt: 6H); 2.36 (dd, J=16.5 and 3.5 Hz:1H); from 2.70 to 2.90 (mt: 2H); 3.13 (mt: 2H); 3.20 (mt: 2H); from 3.35to 3.55 (mt: 2H); 3.91 (s: 3H); 5.32 (broad t, J=7.5 Hz: 1H); 7.10 (dd,J=5.5 and 3.5 Hz: 1H); 7.28 (dd, J=3.5 and 1 Hz: 1H); 7.38 (dd, J=9 and3 Hz: 1H); 7.68 (dd, J=5.5 and 1 Hz: 1H); 7.94 (mt: 1H); 7.96 (d, J=9Hz: 1H); 8.70 (d, J=1.5 Hz: 1H); 10.15 (unresolved complex: 1H).

[0331] Stereoisomer VI

[0332] A solution of 0.36 g of methyl4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-(thienylthio)ethyl)]piperidine-3-acetatestereoisomer VI) in 10-cm³ of dioxane and 1.7-cm³ of a 1 N aqueoussodium hydroxide solution was heated with stirring at a temperature inthe region of 60° C., for 2 hours. After concentrating the reactionmixture under reduced pressure (5 kPa) at a temperature in the region of40° C., the residue obtained was taken up in 10-cm³ of water, acidifiedwith an aqueous acetic acid solution in order to obtain a pH equal to 6.The suspension was taken up in twice 10-cm³ of dichloromethane and thenthe organic phase was separated after settling out, dried over magnesiumsulfate, filtered, concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. The product obtained was thenstirred in 20-cm³ of acetone; a 4 N hydrochloric acid solution indioxane was poured in. The precipitate formed was concentrated underreduced pressure (5 kPa) at a temperature in the region of 40° C. Theresidue obtained was then taken up in acetone several times whileevaporating according to the conditions described above at each stage,and then dried in an oven under a reduced pressure (10 Pa) at atemperature in the region of 20° C. for 48 hours. 0.325 g of4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-aceticacid dihydrochloride (stereoisomer VI) were obtained in the form of awhite solid. (αD²⁰=+29.8° +/−0.8 in methanol at 0.5%).

[0333]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.30 to2.20 (mt: 9H); 2.46 (mt: 1H); from 2.70 to 2.95 (mt: 2H); from 3.10 to3.30 (mt: 4H); from 3.35 to 3.65 (mt: 2H); 3.91 (s: 3H); 5.32 (dd, J=8and 6 Hz: 1H); 7.12 (dd, J=5.5 and 3.5 Hz: 1H); 7.31 (dd, J=3.5 and 1Hz: 1H); 7.40 (dd, J=9 and 3 Hz: 1H); 7.72 (dd, J=5.5 and 1 Hz: 1H);7.96 (d, J=9 Hz: 1H); 7.98 (mt: 1H); 8.70 (d, J=1.5 Hz: 1H); 9.93(unresolved complex: 1H).

[0334] Stereoisomer VII

[0335] A solution of 0.39 g of methyl4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-(thienylthio)ethyl)]piperidine-3-acetate(stereoisomer VII) in 10-cm³ of dioxane and 1.8-cm³ of a 1 N aqueoussodium hydroxide solution was heated, with stirring at a temperature inthe region of 60° C., for 2 hours. After concentrating the reactionmixture under reduced pressure (5 kPa) at a temperature in the region of40° C., the residue obtained was taken up in 10-cm³ of water andacidified with an aqueous acetic acid solution in order to obtain a pHequal to 6. The suspension was taken up in 20-cm³ of dichloromethane andthen the organic phase was separated after settling out, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure (5kPa) at a temperature in the region of 40° C. The product obtained wasthen stirred in 20-cm³ of acetone; a 4 N hydrochloric acid solution indioxane was then poured in. The precipitate formed was concentratedunder reduced pressure (5 kPa) at a temperature in the region of 40° C.The residue obtained was then taken up in acetone several times whileevaporating according to the conditions described above at each stage,and then dried in an oven under a reduced pressure (10 Pa) at atemperature in the region of 20° C. for 48 hours. 0.4 g of4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-aceticacid dihydrochloride (stereoisomer VII) were obtained in the form of awhite solid (αD²⁰=−27.1° +/−0.7 in methanol at 0.5%).

[0336]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.30 to2.20 (mt: 9H); 2.45 (mt: 1H); from 2.70 to 2.95 (mt: 2H); from 3.10 to3.30 (mt: 4H); from 3.35 to 3.70 (mt: 2H); 3.91 (s: 3H); 5.32 (dd, J=8and 6 Hz: 1H); 7.10 (dd, J=5.5 and 3.5 Hz: 1H); 7.30 (dd, J=3.5 and 1Hz: 1H); 7.39 (dd, J=9 and 3 Hz: 1H); 7.71 (dd, J=5.5 and 1 Hz: 1H);7.95 (d, J=9 Hz: 1H); 7.97 (mt: 1H); 8.68 (d, J=1.5 Hz: 1H); 9.96(unresolved complex: 1H).

[0337] b) Synthesis of Stereoisomers of Methyl4-[3-hydroxy-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2-(thienylthio)ethyl)]piperidine-3-acetate

[0338] A mixture of 11.9 g of methyl4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetatehydrochloride, 4.5 g of 2-(2-bromoethylthio)thiophene, 3 g of potassiumiodide, 7.5 g of potassium carbonate and 5-cm³ of trietylamine in200-cm³ of acetonitrile and 100-cm³ of dimethylformamide was heated,with stirring, for 16 hours at a temperature in the region of 65° C. Thereaction mixture was filtered and the filtrate was concentrated todryness under reduced pressure (1 kPa) at a temperature in the region of50° C. The evaporation residue was purified by chromatography under anargon pressure of 40 kPa, on a column of silica gel (particle size 40-60μm; diameter 8 cm, height 40 cm), eluting with a cyclohexane-ethylacetate (50/50 by volume) mixture, collecting 200-cm³ fractions afterthe passage of 3 dm³ of a cyclohexane-ethyl acetate (50/50 by volume)mixture. Fractions 20 to 40 were combined and then concentrated todryness under reduced pressure (2 kPa) at a temperature in the region of40° C. in order to obtain 3.1 g of a mixture of stereoisomers I, II,III, IV, in the form of a yellow oil. Fractions 48 to 90 were combinedand then concentrated to dryness under reduced pressure (2 kPa) at atemperature in the region of 40° C. in order to obtain 3.8 g of amixture of stereoisomers V, VI, VII, VIII, in the form of a yellow oil.

[0339] The absolute stereochemistry of each stereoisomer (esters) calledhereinafter I, II, III, IV V, VI, VII, VIII is not known.

[0340] Starting with the Mixture of Stereoisomers I, II, III, IVObtained Above, the Separation of Each Stereoisomer was Carried Out byHPLC:

[0341] The separation of 2 pairs of stereoisomers (I+II) and (III+IV)was carried out on a stationary chiral phase starting with 22.7 g of theI, II, III, IV mixture described above in Example 8b, (type of phase:chiracel OD; particle size 20 μmm; diameter 80 mm; mixture of thestationary phase 1.2 kg), under a pressure of 600 kPa, the mobile phasewas composed of a mixture of heptane-2-propanol (90/10 by volume) havinga flow rate of 160-cm³ per minute and the UV detector wavelength was setat 265 nm. The fractions containing a first pair of diastereoismersnoted (I+II) were combined and concentrated to dryness under reducedpressure (2 kPa) at a temperature in the region of 40° C. and 1.3 g wereobtained in the form of an oil with a recovery rate equal to 96%. Thefractions containing the second pair of diastereoismers noted (I+IV)were combined and concentrated to dryness under reduced pressure (2 kPa)at a temperature in the region of 40° C. and 1.03 g thereof wereobtained in the form of an oil with a recovery rate equal to 76%. Next,the products of each pair of stereoisomers (I−II and III−IVrespectively) were separated on a chiralpak AD column (particle size 20μmm; diameter 80 mm; mass of the stationary phase 1.2 kg) under apressure of 800 kPa, the mobile phase was composed of a mixture ofheptane-ethanol (90/10 by volume) having a flow rate of 200-cm³ perminute and the UV detector wavelength was set at 280 nm. The fractionscontaining each product were isolated and then concentrated underreduced pressure (2 kPa) at a temperature in the region of 40° C.; 0.632g of the stereoisomer I, 0.553 g of the stereoisomer II, 0.463 g of thestereoisomer III, 0.46 g of the stereoisomer IV were thus obtained.

[0342] NMR spectrum of stereoisomer I: ¹H (300 MHz, (CD₃)₂SO d6, δ inppm): from 0.85 to 1.55 (mt: 6H); from 1.75 to 2.10 (mt: 6H); from 2.35to 2.55 (mt: 2H); from 2.55 to 2.80 (mt: 2H); 2.87 (t, J=7 Hz: 2H); 3.50(s: 3H); 3.89 (s: 3H); 5.33 (broad t, J=7 Hz: 1H); 5.82 (broad s: 1H);7.04 (dd, J=5.5 and 3.5 Hz: 1H); 7.15 (dd, J=3.5 and 1.5 Hz: 1H); 7.38(dd, J=9 and 3 Hz: 1H); 7.60 (dd, J=5.5 and 1.5 Hz: 1H); from 7.90 to8.00 (mt: 2H); 8.68 (d, J=2 Hz: 1H).

[0343] HPLC condition: Chiralpack® column, flow rate 1-cm³/min, elutioncondition from 0 to 13 mim: ethanol-heptane (7/93 by volume) from 13 to28 min (in a gradient) ethanol-heptane (15/93 by volume) from 28 to 35min (in a gradient) ethanol-heptane (7/93 by volume) Retention time:24.13 min

[0344] NMR spectrum of stereoisomer II: ¹H (300 MHz, (CD₃)₂SO d6, δ inppm): from 1.00 to 1.55 (mt: 6H); from 1.70 to 2.15 (mt: 5H); 2.21 (dd,J=16 and 3 Hz: 1H); from 2.30 to 2.60 (mt: 2H); 2.67 (mt: 2H); 2.89 (t,J=7 Hz: 2H); 3.59 (s: 3H); 3.90 (s: 3H); 5.34 (mt: 1H); 5.83 (very broadd, J=3 Hz: 1H); 7.05 (dd, J=5.5 and 3.5 Hz: 1H); 7.17 (broad dd, J=3.5and 1.5 Hz: 1H); 7.39 (dd, J=9 and 3 Hz: 1H); 7.61 (dd, J=5.5 to 1.5 Hz:1H); 7.96 (d, J=9 Hz: 1H); 7.99 (mt: 1H); 8.69 (broad s: 1H).

[0345] HPLC condition: Chiralpack® column, flow rate 1-cm³/min, elutioncondition from 0 to 13 mim: ethanol-heptane (7/93 by volume) from 13 to28 min (in a gradient) ethanol-heptane (15/93 by volume) from 28 to 35min (in a gradient) ethanol-heptane (7/93 by volume) Retention time:29.04 min

[0346] NMR spectrum of stereoisomer III: ¹H (300 MHz, (CD₃)₂SO d6, δ inppm): from 1.00 to 1.55 (mt: 6H); from 1.70 to 2.15 (mt: 5H); 2.21 (dd,J=16 and 3.5 Hz: 1H); from 2.30 to 2.60 (mt: 2H); 2.67 (mt: 2H); 2.88(t, J=7 Hz: 2H); 3.58 (s: 3H); 3.90 (s: 3H); 5.33 (mt: 1H); 5.82 (broads: 1H); 7.04 (dd, J=5.5 and 3.5 Hz: 1H); 7.16 (dd, J=3.5 and 1.5 Hz:1H); 7.38 (dd, J=9and 3 Hz: 1H); 7.59 (dd, J=5.5 and 1.5 Hz: 1H); 7.96(d, J=9 Hz: 1H); 7.97 (mt: 1H); 8.68 (broad d, J=1.5 Hz: 1H).

[0347] HPLC condition: Chiralpack® column, flow rate 1-cm³/min, elutioncondition from 0 to 13 mim: ethanol-heptane (7/93 by volume) from 13 to28 min (in a gradient) ethanol-heptane (15/93 by volume) from 28 to 35min (in a gradient) ethanol-heptane (7/93 by volume) Retention time: 23min

[0348] NMR spectrum of stereoisomer IV: ¹H (300 MHz, (CD₃)₂SO d6, δ inppm): from 0.90 to 1.55 (mt: 6H); from 1.75 to 2.10 (mt: 6H); from 2.35to 2.55 (mt: 2H); from 2.55 to 2.80 (mt: 2H); 2.87 (t, J=7 Hz: 2H); 3.50(s: 3H); 3.90 (s: 3H); 5.35 (mt: 1H); 5.83 (d, J=3 Hz: 1H); 7.04 (dd,J=5.5 and 3.5 Hz: 1H); 7.15 (broad dd, J=3.5 and 1.5 Hz: 1H); 7.38 (dd,J=9 and 3 Hz: 1H); 7.60 (broad dd, J=5.5 and 1.5 Hz: 1H); from 7.90 to8.00 (mt: 2H); 8.69 (broad s: 1H).

[0349] HPLC condition: Chiralpack® column, flow rate 1-cm³/min, elutioncondition from 0 to 13 mim: ethanol-heptane (7/93 by volume) from 13 to28 min (in a gradient) ethanol-heptane (15/93 by volume) from 28 to 35min (in a gradient) ethanol-heptane (7/93 by volume) Retention time:25.38 min

[0350] Starting with the Mixture of Stereoisomers V, VI VII, VIIIObtained Above, the Separation of Each Stereoisomer was Carried Out byHPLC

[0351] The separation of the 2 pairs of stereoisomers was carried out ona C18 stationary phase starting with 3.5 g of the V, VI, VII, VIIImixture described above (type of phase: KROMACIL® C18; particle size 7μm; diameter 4.6 mm; mass of the stationary phase 1 kg), under apressure of 5 000 kPa, the mobile phase was composed of a mixture ofwater-acetonitrile-methanol-trifluoroacetic acid (60/15/25/0.05 byvolume) having a flow rate of 140-cm³ per minute and the UV detectorwavelength was set at 254 nm. The fractions containing the first pair ofstereoisomers noted (V+VIII) were combined and concentrated to drynessunder reduced pressure (2 kPa) at a temperature in the region of 40° C.and 1.84 g thereof were obtained in the form of an oil. The fractionscontaining the second pair of stereoisomers noted (VI+VII) were combinedand concentrated to dryness under reduced pressure (2 kPa) at atemperature in the region of 40° C. and 1.42 g thereof were obtained inthe form of an oil. Next, the enantiomers of the pair of stereoisomers(V+VIII) were separated on a CHIRALPAK® AS column (particle size 20 μm;diameter 80 mm; mass of the stationary phase 1.2 kg) under a pressure of290 kPa, the mobile phase was composed of a mixture ofisopropanol-heptane-triethylamine (10/90/0.1 by volume) having a flowrate of 110-cm³ per minute and the UV detector wavelength was set at 265nm. The fractions containing each enantiomer were isolated and thenconcentrated under a reduced pressure (2 kPa) at a temperature in theregion of 40° C.; 0.5 g of stereoisomer V were thus obtained, theenantiomers of the pair of stereoisomers VI+VII were separated on an OCtype CHIRALCEL® column (particle size 10 μm; diameter 60 mm; mass of thestationary phase 600 g) under a pressure of 230 kPa, the mobile phasewas composed of an ethanol-heptane-triethylamine (10/90/0.1 by volume)mixture having a flow rate of 90-cm³ per minute and the UV detectorwavelength was set at 265 nm. The fractions containing each enantiomerwere isolated and then concentrated under reduced pressure (2 kPa) at atemperature in the region of 40° C.; 0.36 g of stereoisomer VI and 0.68g of stereoisomer VII were thus obtained.

[0352]¹H NMR spectrum stereoisomer V: (300 MHz, (CD₃)₂SO d6, δ in ppm):from 0.80 to 2.00 (mt: 8H); 2.08 (broad dd, J=16.5 and 8 Hz: 1H); 2.35(dd, J=16.5 and 4 Hz: 1H); from 2.20 to 3.30 (mt: 8H); 3.55 (s: 3H);3.92 (s: 3H); 5.33 (mt: 1H); 5.88 (d, J=4 Hz: 1H); 7.08 (dd, J=5.5 and3.5 Hz: 1H); 7.25 (broad d, J=3.5 Hz: 1H); 7.42 (dd, J=9 and 3 Hz: 1H);7.68 (dd, J=5.5 and 1 Hz: 1H); 7.95 (mt: 1H); 7.97 (d, J=9 Hz: 1H); 8.69(broad d, J=1.5 Hz: 1H); from 8.90 to 10.00 (unresolved complex: 1H).

[0353] HPLC condition: separation on Chiralpak AS 20 μm phase. Elutioncondition: heptane, ethanol, trethylamine (85/15/0.1% volume); 1 ml/minUV 254 nm Retention time: 9.37 min

[0354]¹H NMR spectrum stereoisomer VI: (300 MHz, (CD₃)₂SO d6, δ in ppm):from 1.00 to 2.65 (mt: 12H); 2.06 (dd, J=15.5 and 7.5 Hz: 1H); 2.40 (dd,J=15.5 and 4 Hz: 1H); from 2.65 to 2.90 (mt: 2H); 2.91 (broad t, J=7 Hz:2H); 3.54 (s: 3H); 3.90 (s: 3H); 5.32 (mt: 1H); 5.84 (d, J=4 Hz: 1H);7.05 (dd, J=5.5 and 3.5 Hz: 1H); 7.16 (dd, J=3.5 and 1.5 Hz: 1H); 7.39(dd, J=9 and 3 Hz: 1H); 7.61 (dd, J=5.5 and 1.5 Hz: 1H); 7.96 (d, J=9Hz: 1H); 7.99 (mt: 1H); 8.68 (broad d, J=1.5 Hz: 1H).

[0355] HPLC conditions for the separation on a Chiracel OC 10 μm columnElution condition: heptane, ethanol, triethylamine (90/10/0.1% byvolume); 1 ml/min; UV 254 nm. Retention time: 17.5 min

[0356]¹H NMR spectrum stereoisomer VII: (300 MHz, (CD₃)₂SO d6, δ inppm): from 1.00 to 2.65 (mt: 12H); 2.05 (dd, J=15 and 7.5 Hz: 1H); 2.40(dd, J=15 and 4 Hz: 1H); 2.79 (mt: 2H); 2.93 (broad t, J=7 Hz: 2H); 3.56(s: 3H); 3.90 (s: 3H); 5.31 (mt: 1H); 5.84 (d, J=4 Hz: 1H); 7.05 (dd,J=5.5 and 3.5 Hz: 1H); 7.19 (broad d, J=3.5 Hz: 1H); 7.40 (dd, J=9 and 3Hz: 1H); 7.62 (dd, J=5.5 and 1 Hz: 1H); 7.96 (d, J=9 Hz: 1H); 7.99 (mt:1H); 8.68 (broad d, J=1.5 Hz: 1H).

[0357] HPLC Conditions for the Separation on a Chiracel OC 10 μm Column

[0358] Elution condition: heptane, ethanol, triethylamine (90/10/0.1% byvolume); 11 ml/min; UV 254 nm. Retention time: 23.76 min

EXAMPLE 9

[0359] a)(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxy-quinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidin-3-yl}aceticAcid Dihydrochloride

[0360] A mixture of 0.97 g of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxy-quinoline-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidin-3-yl-acetatein 30-cm³ of dioxane and 4-cm³ of a 1 N aqueous sodium hydroxidesolution was heated at a temperature in the region of 50° C. withstirring for 18 hours. After cooling in the vicinity of 20° C., thereaction mixture was concentrated to dryness under reduced pressure (2kPa) at a temperature in the region of 50° C. The evaporation residuewas taken up in 10-cm³ of distilled water, acidified with a sufficientvolume of a 1 N aqueous hydrochloric acid solution in order to obtain apH in the region of 4. The mixture was extracted twice with 15-cm³ ofdichloromethane and the organic phase was dried over magnesium sulfate,filtered and concentrated to dryness according to the same conditionsdescribed above. The residue was taken up in 5-cm³ of acetone and 1-cm³of a hydrochloric acid solution in dioxane and then concentrated todryness under reduced pressure (1 kPa) at a temperature in the region of50° C. The residue was again taken up in 5-cm³ of acetone andconcentrated to dryness according to the same conditions describedabove. 0.69 g of(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidin-3-yl-aceticacid dihydrochloride were obtained in the form of a solid melting in thevicinity of 135° C.

[0361] Infrared spectrum: (KBr tablet): 3126; 2938; 2541; 2022; 1720;1628; 1604; 1555; 1498; 1448; 1421; 1308; 1243; 1180; 1141; 1097; 1000;870 and 780 cm-1

[0362] b) Methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidin-3-yl-acetate

[0363] A mixture of 1.7 g of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate,0.077 g of copper iodide, 1.2 g of 1-bromo-2,3,5-trifluorobenzene, 0.23g of 2-tetrakis(triphenyl-phosphine)palladium(0) in 17-cm³ oftriethylamine was heated at a temperature in the region of 80° C. withstirring for 8 hours. After cooling in the region of 20° C., thereaction mixture was concentrated to dryness under reduced pressure (2kPa) at a temperature in the region of 50° C. The evaporation residuewas taken up in 20-cm³ of ethyl acetate, washed 3 times with 15-cm³ ofdistilled water, dried over magnesium sulfate, filtered and concentratedto dryness according to the same conditions described above. The residuewas purified by chromatography under an argon pressure of 50 kPa, on acolumn of silica gel (particle size 40-60 μm; diameter 3 cm), elutingwith a mixture of cyclohexane-ethyl acetate (80/20 by volume) andcollecting 15-cm³ fractions. Fractions 48 to 78 were combined and thenconcentrated to dryness according to the same conditions describedabove. 0.97 g of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidin-3-yl}acetatewere obtained in the form of an oil.

[0364] Infrared spectrum (CCl₄): 3618; 3089; 2935; 2804; 2766; 2223;1737; 1623; 1508; 1496; 1232; 1166; 1132; 1075; 999; 861 and 834 cm-1

EXAMPLE 10

[0365] a)(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylicAcid Dihydrochloride

[0366] A solution of 630 mg of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylate,6-cm³ of dioxane and 3-cm³ of a 1 N aqueous sodium hydroxide solutionwas heated with stirring at a temperature in the region of 60° C. for 2hours. 3-cm³ of a 1 N aqueous sodium hydroxide solution were added andthe solution was heated for 1 hour at 60° C. After concentrating thereaction mixture under reduced pressure (5 kPa) at a temperature in theregion of 40° C., the residue obtained was taken up in 20-cm³ of waterand 20-cm³ of diethyl ether. The aqueous phase was separated aftersettling out and was then acidified by pouring in 6-cm³ of 1 Nhydrochloric acid. The white precipitate formed was extracted with150-cm³ of ethyl acetate. The organic phase was washed twice with 10-cm³of a saturated aqueous sodium chloride solution and dried over magnesiumsulfate, filtered, and then concentrated under reduced pressure (5 kPa)at a temperature in the region of 40° C. 499 mg of(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylicacid were obtained in the form of a white solid.

[0367]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6 with, δ in ppm). A mixtureof stereoisomers in the proportions 50/50 was observed.

[0368] * from 0.90 to 2.25 (mt: 10H); from 2.45 to 2.65 (mt: 2H); from2.70 to 3.05 (mt: 4H); 3.92 (s: 3H); 5.31 (mt: 1H); from 5.50 to 6.20(broad unresolved complex: 1H); 7.04 (mt: 1H); 7.18 (mt: 1H); 7.38 (mt:1H); 7.59 (mt: 1H); from 7.90 to 8.05 (mt: 2H); 8.67 (mt: 1H); from11.50 to 13.50 (very broad unresolved complex).

[0369] b) Methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylate

[0370] 0.74-cm³ of triethylamine was added to a solution composed of1.17 g of methyl (3RS, 4RS)4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)piperidine-3-carboxylatedihydrochloride in 20-cm³ of acetonitrile and 10-cm³ of DMF, followed by638 mg of 2-(2-bromoethylthio)thiophene in 10-cm³ of acetonitrile, 1 gof potassium carbonate and 431 mg of potassium iodide. The mixture wasstirred for 15 hours at a temperature in the region of 65° C. under aninert atmosphere. After cooling to about 20° C., the reaction mixturewas filtered on sintered glass. The filtrate was taken up in 100-cm³ofacetonitrile and concentrated under reduced pressure (5 kPa). Theresidue was taken up in 200-cm³ of ethyl acetate and 100-cm³ of water.The organic phase was separated after settling out, washed with twice75-cm³ of a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure (5kPa) at a temperature in the region of 40° C. The residue obtained waspurified by chromatography, under a nitrogen pressure of 50 kPa, on acolumn of silica gel (particle size 20-45 μ; diameter 2 cm; height 40cm), eluting with a mixture of cyclohexane-ethyl acetate (25/75 byvolume) and collecting 50-cm³ fractions. Fractions 6 to 8 wereconcentrated. 630 mg of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylatewere obtained in the form of a colorless oil.

[0371] Infrared spectrum (CCl₄): 3616; 2950; 2811; 2770; 1739; 1623;1508; 1497; 1354; 1232; 1158; 1133; 1034; 907; 834 and 700 cm-1

[0372] c) Methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylateDihydrochloride

[0373] A solution of 1.26 g of(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylicacid in 50-cm³ of methanol was cooled to a temperature in the region of−25° C. with stirring and under an inert atmosphere. 1.6-cm³ of thionylchloride were added to this solution over 25 minutes. The mixture wasbrought to a temperature in the region of 20° C., while the stirring wascontinued for a further 48 hours. The reaction mixture was concentratedunder reduced pressure (5 kPa) at a temperature in the region of 40° C.,taken up in 100-cm³ of toluene and the mixture was again concentratedunder reduced pressure (5 kPa). The residue was taken up in 50-cm³ ofdiisopropyl ether, triturated and concentrated to dryness under reducedpressure (5 kPa). 1.17 g of methyl(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylatedihydrochloride were obtained in the form of a yellow powder.

[0374] Infrared spectrum (KBr tablet):3415; 3129; 2949; 2772; 2473;2022; 1733; 1622; 1603; 1555; 1496; 1420; 1307; 1242; 1172; 1019; 871and 795 cm-1

[0375] d)(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylicAcid

[0376] A solution of 1.77 g of methyl(3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylate,140-cm³ of anhydrous dimethyl sulfoxide and 30-cm³ of anhydroustert-butanol was stirred under an inert atmosphere free of water at 20°C. This solution was purged with pure oxygen until the reaction mixturebecomes saturated. A solution containing 1.75 g of potassiumtert-butoxide in 10-cm³ of anhydrous tert-butanol was then added. Oxygenwas again introduced by bubbling for a further 1 hour and 10 minuteswith vigorous stirring. The solution obtained was purged with nitrogenand then cooled to 0° C. 1-cm³ of pure acetic acid in 100-cm³ of waterwas then added followed by 100-cm³ of water and 500-cm³ of ether. Theorganic phase was separated after settling out, washed 7 times with100-cm³ of water and 3 times with 100-cm³ of a saturated aqueous sodiumchloride solution. The aqueous phase was extracted with 400-cm³ of ethylacetate, washed 7 times with 75-cm³ of water and 3 times with 75-cm³ ofa saturated aqueous sodium chloride solution. The 2 organic phases werecombined, dried over magnesium sulfate, filtered and concentrated todryness under reduced pressure (5 kPa) at a temperature in the region of40° C. 1.26 g of(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylicacid were obtained in the form of a white foam.

[0377]¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 with, at a temperature of383 K, δ in ppm). A mixture of stereoisomers was observed.

[0378] * from 0.85 to 2.30 (mt: 16H); from 2.60 to 3.25 (mt: 5H); 3.88(mt: 1H); 3.94 (s: 3H); 4.00 (broad dd, J=14 and 3 Hz: 1H); 5.35 (mt:1H); 7.38 (mt: 1H); from 7.90 to 8.00 (mt: 2H); 8.63 (broad s: 1H).

[0379] e) Methyl(3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylate

[0380] A solution of 1.45 g of methyl(3RS,4RS)-1-(tert-butyloxycarbonyl)-4-allylpiperidine-3-carboxylate in20-cm³ of tetrahydrofuran was slowly added, at a temperature in theregion of 0° C. with stirring and under an inert atmosphere, to 16-cm³of a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran.The mixture was then brought to a temperature in the region of 20° C.while the stirring was continued for a further 4 hours. 1.52 g of4-iodo-3-fluoro-6-methoxyquinoline in solution in 40-cm³ oftetrahydrofuran were added, followed by 100 mg ofpalladiumdiphenylphosphinoferrocene chloride and finally 3.18 g oftribasic potassium phosphate. The reaction mixture was heated for 15hours under reflux and then filtered in the hot state on sintered glass.The filtrate was taken up in 50-cm³ of ethyl acetate and concentrated todryness under reduced pressure (5 kPa). The residue was taken up in75-cm³ of ethyl acetate and 40-cm³ of water. The organic phase wasseparated after settling out, washed twice with 40-cm³ of a saturatedaqueous sodium chloride solution, dried over magnesium sulfate, filteredand then concentrated under reduced pressure (5 kPa) at a temperature inthe region of 40° C. The residue was purified by chromatography, under anitrogen pressure of 50 kPa, on a column of silica gel (particle size20-45 μ; diameter 2.5 cm; height 40 cm), eluting with a mixture ofcyclohexane-ethyl acetate (75/25 by volume) and collecting 50-cm³fractions. Fractions 16 to 22 were combined and then concentrated. 1,77g of methyl(3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylatewere obtained in the form of a colorless oil.

[0381]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6 with, δ in ppm): from 1.25to 1.90 (mt: 16H); 2.61 (mt: 1H); from 2.65 to 3.25 (mt: 4H); 3.47(broad s: 3H); from 3.60 to 4.05 (mt: 2H); 3.96 (s: 3H); 7.36 (d, J=3Hz: 1H); 7.40 (dd, J=9 and 3 Hz: 1H); 7.97 (d, J=9 Hz: 1H); 8.70 (broads: 1H).

[0382] f) Methyl(3RS,4RS)-1-(tert-butyloxycarbonyl)-4-allylpiperidine-3-carboxylate

[0383] 11.34 g of tributyltin hydride were added to a solution of 10.1 gof methyl1-(tert-butyloxycarbonyl)-4-allyl-4-(methoxallyl)hydroxypiperidine-3-carboxylatein 250-cm³ of toluene under an inert atmosphere and at a temperatureclose to 20° C. 25 mg of AIBN were then added and the reaction mixturewas heated at the reflux temperature of the solvent for 1 hour. Themixture was cooled to a temperature close to 20° C., concentrated todryness under reduced pressure (5 kPa). The residue was taken up in50-cm³ of dichloromethane and then purified by chromatography, under anitrogen pressure of 50 kPa, on a column of silica gel (particle size20-45 μ; diameter 7 cm; height 40 cm), eluting with a mixture ofcyclohexane-ethyl acetate (75/25 by volume) and collecting 200-cm³fractions. Fractions 6 to 8 were combined, and then concentrated. 1.4 gof methyl(3RS,4RS)-1-(tert-butyloxycarbonyl)-4-allylpiperidine-3-carboxylate wereobtained in the form of a colorless oil.

[0384]¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 with, at a temperature of353 K, δ in ppm): from 1.35 to 1.50 (mt: 1H); 1.40 (s: 9H); from 1.65 to1.80 (mt: 1H); 1.89 (mt: 1H); from 1.95 to 2.20 (mt: 2H); 2.62 (mt: 1H);2.97 (mt: 1H); 3.22 (dd, J=14 and 4 Hz: 1H); 3.60 (s: 3H); from 3.65 to3.80 (mt: 1H); 3.91 (broad dd, J=14 and 5 Hz: 1H); 5.02 (mt: 2H); from5.65 to 5.85 (mt: 1H).

[0385] g) Methyl1-(tert-butyloxycarbonyl)-4-allyl-4-(methoxallyl)hydroxypiperidine-3-carboxylate

[0386] 7.57 g of dimethylaminopyridine were added, under an inertatmosphere, to a solution of 9.4 g of methyl1-(tert-butyloxycarbonyl)-4-allyl-4-hydroxypiperidine-3-carboxylate in120-cm³ of acetonitrile and then 5.7-cm³ of oxalyl chloride were pouredin over 20 minutes. After stirring for 15 hours at a temperature closeto 20° C., 1.22 g of dimethylaminopyridine were added followed by0.92-cm³ of oxalyl chloride. The stirring was maintained for 15 hours atthe same temperature. This addition procedure was repeated once more andthe stirring was continued for 6 hours. The reaction mixture was takenup in 200-cm³ of ethyl acetate and 200-cm³ of a saturated aqueous sodiumbicarbonate solution. The organic phase was separated after settlingout, washed with twice 100-cm³ of a saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and filtered on sintered glass.The filtrate was stirred for one hour with 11 g of silica, filtered onsintered glass, taken up in 20 g of silica and 300-cm³ of ethyl acetate,and then concentrated under reduced pressure (5 kPa) at a temperature inthe region of 40° C. 12.15 g of methyl1-(tert-butyloxycarbonyl)-4-allyl-4-(methoxallyl)hydroxypiperidine-3-carboxylatewere obtained in the form of a beige oil.

[0387] Infrared spectrum (CCl₄): 3082; 2980; 2954; 1775; 1748; 1699;1641; 1424; 1392; 1367; 1245; 1202; 1162; 1142; 993 and 925 cm-1

[0388] h) Methyl1-(tert-butyloxycarbonyl)-4-allyl-4-hydroxypiperidine-3-carboxylate

[0389] 101.66 g of methyl1-(tert-butyloxycarbonyl)-4-oxopiperidine-3-carboxylate were added,under an inert atmosphere and at a temperature close to 20° C., to 2.156liters of a saturated aqueous solution of ammonium chloride and of THF(10/1 by volume) of THF. 34.73-cm³ of allyl bromide were then added,followed by 77.51 g of zinc while maintaining the temperature below 30°C. A solution of 69.47-cm³ of allyl bromide in 50-cm³ of THF was thenpoured in dropwise. After stirring for 3 hours at a temperature close to20° C., the reaction was incomplete. 77.51 g of zinc were again addedand then 104-cm³of allyl bromide were poured in dropwise while thetemperature was maintained below 30° C. The stirring was maintained at atemperature close to 20° C. for 15 hours, after which the reaction wasstill incomplete. 35 g of zinc were again added and then 55-cm³ of allylbromide were poured in dropwise while the temperature was maintainedbelow 30° C. The stirring was maintained at a temperature close to 20°C. for 4 hours, after whichthe reaction was still incomplete. 10 g ofzinc were again added and then 25-cm³ of allyl bromide were poured indropwise while the temperature was maintained below 30° C. The stirringwas maintained at a temperature close to 20° C. for 2 hours. Thereaction mixture was taken up in 900-cm³ of a 1 N HCl solution and 2liters of ethyl ether and filtered on sintered glass. The filtrate waswashed with 3 times 500-cm³ of etyl ether. The organic phase was washedwith a saturated aqueous sodium chloride solution, dried over magnesiumsulfate and concentrated to dryness under reduced pressure (5 kPa). Ayellow oil was obtained, which was purified by chromatography, under anitrogen pressure of 50 kPa, on a column of silica gel (particle size20-45 μ; diameter 12 cm; height 60 cm), eluting with a mixture ofcyclohexane-ethyl acetate (80/20 by volume) and collecting 200-cm³fractions. Fractions 51 to 75 were combined and then concentrated. 63.5g of methyl1-(tert-butyloxycarbonyl)-4-allyl-4-hydroxypiperidine-3-carboxylate wereobtained in the form of a light yellow oil.

[0390] Infrared spectrum (CCl₄): 3513; 3078; 2980; 2954; 1697; 1641;1423; 1392; 1366; 1200; 1163; 962 and 919 cm-1

[0391] i) Methyl 1-(tert-butyloxycarbonyl)-4-oxopiperidine-3-carboxylate

[0392] 65.27-cm³ of trietylamine were added, with stirring, to asuspension of 89.93 g of 3-methoxycarbonyl-4-piperidone hydrochloride(at 98% purity) in 900-cm³ of dichloromethane, cooled to a temperaturein the region of 0° C., followed by 91.12 g of di-tert-butyl dicarbonatesolubilized beforehand in 400-cm³ of dichloromethane. The mixture wasstirred for 12 hours at a temperature close to 20° C. The trietylaminehydrochloride was filtered, and then the filtrate was washed 3 timeswith 500-cm³ of water and then twice with 500-cm³ of a saturated aqueoussodium chloride solution. The organic phase was filtered on sinteredmaterial containing fine silica, dried over sodium sulfate, filtered andthen concentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. 101.66 g of methyl1-(tert-butyloxycarbonyl)-4-oxopiperidine-3-carboxylate were obtained inthe form of a light yellow oil.

[0393] Infrared spectrum (CH₂Cl₂): 2982; 2932; 2872; 1740; 1691; 1664;1622; 1477; 1468; 1423; 1367; 1338; 1309; 1235; 1200; 1167; 1123; 1064cm⁻¹

[0394] Another embodiment of the present invention relates to thepharmaceutical compositions comprising at least onequinolylpropylpiperidine derivative or compound according to theinvention, where appropriate in the form of a salt, in the pure state orin the form of a combination with one or more compatible andpharmaceutically acceptable diluents or adjuvants.

[0395] The compositions according to the invention may be used orally,parenterally, topically, rectally, or as aerosols.

[0396] As solid compositions for oral administration, tablets, pills,gelatin capsules, powders, or granules may be used. In thesecompositions, the active product according to the invention can be mixedwith one or more inert diluents or adjuvants such as sucrose, lactose,or starch. These compositions may comprise substances other than thediluents, for example, a lubricant such as magnesium stearate or acoating intended for a controlled release.

[0397] As liquid compositions for oral administration, solutions thatwere pharmaceutically acceptable, suspensions, emulsions, syrups andelixirs containing inert diluents such as water or paraffin oil may beused. These compositions may also comprise substances other than thediluents, for example, wetting products, sweeteners, or flavorings.

[0398] The compositions for parenteral administration may be sterilesolutions or emulsions. As solvents or vehicles, water, propyleneglycol, polyethylene glycol, vegetable oils, for example, olive oil,injectable organic esters, for example ethyl oleate, may be used. Thesecompositions may also contain adjuvants, for example, wetting,isotonizing, emulsifying, dispersing and stabilizing agents.

[0399] The sterilization may be carried out in several ways, for examplewith the aid of a bacteriological filter, by irradiation or by heating.They may also be prepared in the form of sterile solid compositions,which may be dissolved at the time of use in sterile water or any otherinjectable sterile medium.

[0400] The compositions for topical administration may be, for example,creams, ointments, lotions or aerosols.

[0401] The compositions for rectal administration include suppositoriesor rectal capsules, which contain, in addition to the active ingredient,excipients such as cocoa butter, semisynthetic glycerides, orpolyethylene glycols.

[0402] The compositions may also be aerosols. For use in the form ofliquid aerosols, the compositions may be stable sterile solutions orsolid compositions dissolved at the time of use in pyrogen-free sterilewater, in saline, or any other pharmaceutically acceptable vehicle. Foruse in the form of dry aerosols intended to be directly inhaled, theactive ingredient may be finely divided and combined with awater-soluble solid diluent or vehicle having a particle size of 30 to80 μm, for example dextran, mannitol or lactose.

[0403] In human therapy, the novel quinolylpropylpiperidine derivativesor compounds according to the invention are useful in the treatment ofinfections of bacterial origin. The doses depend on the desired effectand on the duration of the treatment. The doctor will determine thedosage judged to be most appropriate according to the treatment,according to the age, weight, degree of the infection, and other factorsspecific to the subject to be treated. Generally, the doses range from750 mg to 3 g of active product in 2 or 3 doses per day by the oralroute or from 400 mg to 1.2 g by the intravenous route for an adult.

[0404] As used here, treatment includes therapy for a particulardisease, such as treating an infection. In this respect, treatment canmean successfully eliminating the infection, reducing the effectsassociated with it, and/or reducing its severity. Treatment alsoincludes prevention and prophylaxis of the onset of an infection bytreating patients before an infection occurs, for example in the case ofpatients with wounds, burns, lesions, etc.

[0405] An effective amount of a compound of the invention is an amountsufficient to bring about a desired effect. For example, in the contextof treating an infection, an effective amount of a compound of theinvention would constitute an amount sufficient to achieve any of theeffects described above under treatment of an infection or disease.

[0406] The following example illustrates a composition according to theinvention.

EXAMPLE A

[0407] A liquid composition intended for parenteral use was preparedaccording to customary techniques, comprising:(3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1- 125 mg[2-(thien-2-yl)thioethyl]piperidine-3-acetic acid dihydrochlorideglucose qs 5% sodium hydroxide qs pH = 4-4.5 water for injection qs 50ml

EXAMPLE B

[0408] A liquid composition intended for parenteral use was preparedaccording to customary techniques, comprising:(3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro- 125 mg6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid dihydrochlorideglucose qs 5% sodium hydroxide qs pH = 4-4.5 water for injection qs 50ml

We claim:
 1. A quinolylpropylpiperidine derivative compound of formula(I)

wherein: R₁ represents a hydrogen atom, a halogen atom, or a hydroxyl,amino, alkylamino, dialkylamino, hydroxyamino, alkyloxyamino, oralkylalkyloxyamino radical; R₂ represents a carboxyl, carboxymethyl, orhydroxymethyl radical; R₃ represents an alkyl radical having 1 to 6carbon atoms, which is substituted with: a phenylthio radical, which isoptionally substituted with 1 to 4 substituents chosen from halogen,hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoro-methoxy, carboxyl,alkyloxycarbonyl, cyano, and amino, a cycloalkylthio radical in whichthe cyclic portion contains 3 to 7 members, or a 5- to 6-memberedaromatic heterocyclylthio radical with 1 to 4 heteroatoms chosen fromnitrogen, oxygen, and sulfur, and wherein HENDERSON the 5- to 6-memberedaromatic heterocyclylthio radical is optionally substituted with atleast one radical chosen from halogen, hydroxyl, alkyl, alkyloxy,trifluoromethyl, trifluoro-methoxy, oxo, carboxyl, alkyloxycarbonyl,cyano, and amino; or R₃ represents a propargyl radical substituted with:a phenyl radical, which is optionally substituted with 1 to 4substituents chosen from halogen, hydroxyl, alkyl, alkyloxy,trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano,and amino, a 3- to 7-membered cycloalkyl radical, or a 5- to 6-memberedaromatic heterocyclyl radical with 1 to 4 heteroatoms chosen fromnitrogen, oxygen, and sulfur, and wherein the 5- to 6-membered aromaticheterocyclyl radical is optionally substituted with at least one radicalchosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl,trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, and amino; andR₄ represents an alkyl radical containing 1 to 6 carbon atoms, analkenyl-CH₂—, alkynyl-CH₂—, cycloalkyl, or cycloalkylalkyl radical,wherein the alkenyl and alkynyl portions contain 2 to 6 carbon atoms andthe cycloalkyl portions contain 3 to 8 carbon atoms, wherein the alkylradicals and portions are in the form of a straight or branched chainand contain, unless otherwise stated, 1 to 4 carbon atoms, or adiastereoisomeric form, a cis form, or a trans form of a compound offormula (I) or a mixture thereof, or a salt thereof.
 2. A process forpreparing a quinolylpropylpiperidine derivative compound of formula (I)according to claim 1, comprising: a) condensing an R₃ radical with aquinolylpropylpiperidine derivative of formula (II):

 to obtain a quinolylpropylpiperidine derivative of formula (III):

 wherein for both formula (II) and formula (III), R₃ and R₄ are definedas in claim 1, R′₁ represents a hydrogen atom or a hydroxyl radical, andR′₂ represents a protected carboxyl or carboxymethyl radical; b)optionally, when preparing a compound of formula (I) for which R₁ is ahalogen atom, halogenating a derivative of formula (III) for which R′₁is a hydroxyl radical; c) optionally converting the hydroxyl radical ofR′₁ to an oxo radical, and then to a hydroxyimino or alkyloxyiminoradical to obtain a quinolylpropylpiperidine derivative of formula (IV):

 wherein R′₂, R₃, and R₄ are as defined above, and R₅ is a hydrogen atomor an alkyl radical; d) optionally reducing a derivative of formula (IV)for which R₅ is a hydrogen atom to an amine, and optionally convertingthe amine to a monoalkylated or dialkylated amine; e) optionallyreducing a derivative of formula (IV) for which R₅ is a hydrogen atom toa hydroxylamine; f) optionally reducing a derivative of formula (IV) forwhich R₅ is an alkyl radical to an alkyloxyamine; g) optionally, whenpreparing a compound of formula (I) for which R₁ is alkylalkyloxyamino,alkylating a compound of formula (I) for which R₁ is alkyloxyamino; andh) reducing a protected carboxyl radical R′₂ to a hydroxymethyl radical,to produce a compound of formula (I); or i) eliminating anacid-protected radical R′₂ to produce a carboxyl or carboxymethylradical, to produce a compound of formula (I).
 3. The process accordingto claim 2, further comprising separating at least one diastereoisomerof a compound of formula (I).
 4. The process according to claim 2,further comprising separating a cis or a trans form of a compound offormula (I).
 5. The process according to claim 2, further comprisingconverting a compound of formula (I) into a salt.
 6. The processaccording to claim 3, further comprising converting a diastereoisomer ofa compound of formula (I) into a salt.
 7. The process according to claim4, further comprising converting a cis or a trans form of a compound offormula (I) into a salt.
 8. The process according to claim 2, whereinthe condensation of the R₃ radical with the quinolylpropylpiperidinederivative of formula (II) is carried out by the action of a radical offormula: R₃—X wherein R₃ represents an alkyl radical having 1 to 6carbon atoms, which is substituted with: a phenylthio radical, which isoptionally substituted with 1 to 4 substituents chosen from halogen,hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoro-methoxy, carboxyl,alkyloxycarbonyl, cyano, and amino, a cycloalkylthio radical in whichthe cyclic portion contains 3 to 7 members, or a 5- to 6-memberedaromatic heterocyclylthio radical with 1 to 4 heteroatoms chosen fromnitrogen, oxygen, and sulfur, and wherein the 5- to 6-membered aromaticheterocyclylthio radical is optionally substituted with at least oneradical chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl,trifluoro-methoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, and amino; orR₃ represents a propargyl radical substituted with: a phenyl radical,which is optionally substituted with 1 to 4 substituents chosen fromhalogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy,carboxyl, alkyloxycarbonyl, cyano, and amino, a 3- to 7-memberedcycloalkyl radical, or a 5- to 6-membered aromatic heterocyclyl radicalwith 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur, andwherein the 5- to 6-membered aromatic heterocyclyl radical is optionallysubstituted with at least one radical chosen from halogen, hydroxyl,alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl,alkyloxycarbonyl, cyano, and amino; and X represents a halogen atom, amethylsulfonyloxy radical, a trifluoromethylsulfonyloxy radical or ap-toluenesulfonyloxy radical.
 9. The process according to claim 2,wherein when R₃ represents propargyl substituted with phenyl,cycloalkyl, or heterocyclyl, the condensation reaction is carried out bycondensation of a propargyl halide, followed by substitution of thepropargyl chain with a phenyl, cycloalkyl, or heterocyclyl radical. 10.The process according to claim 8, wherein when R₃ represents propargylsubstituted with phenyl, cycloalkyl, or heterocyclyl, the condensationreaction is carried out by condensation of a propargyl halide, followedby substitution of the propargyl chain with a phenyl, cycloalkyl orheterocyclyl radical.
 11. A quinolylpropylpiperidine derivative offormula (IV):

wherein R′₂ represents a protected carboxyl or carboxymethyl radical; R₃represents an alkyl radical having 1 to 6 carbon atoms, which issubstituted with: a phenylthio radical, which is optionally substitutedwith 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy,trifluoromethyl, trifluoro-methoxy, carboxyl, alkyloxycarbonyl, cyano,and amino, a cycloalkylthio radical in which the cyclic portion contains3 to 7 members, or a 5- to 6-membered aromatic heterocyclylthio radicalwith 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur, andwherein the 5- to 6-membered aromatic heterocyclylthio radical isoptionally substituted with at least one radical chosen from halogen,hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoro-methoxy, oxo,carboxyl, alkyloxycarbonyl, cyano, and amino; or R₃ represents apropargyl radical substituted with: a phenyl radical, which isoptionally substituted with 1 to 4 substituents chosen from halogen,hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl,alkyloxycarbonyl, cyano, and amino, a 3- to 7-membered cycloalkylradical, a 5- to 6-membered aromatic heterocyclyl radical with 1 to 4heteroatoms chosen from nitrogen, oxygen, and sulfur, and wherein the 5-to 6-membered aromatic heterocyclyl radical is optionally substitutedwith at least one radical chosen from halogen, hydroxyl, alkyl,alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl,alkyloxycarbonyl, cyano, and amino; R₄ represents an alkyl radicalcontaining 1 to 6 carbon atoms, an alkenyl-CH₂—, alkynyl-CH₂—,cycloalkyl, or cycloalkylalkyl radical, wherein the alkenyl and alkynylportions contain 2 to 6 carbon atoms and the cycloalkyl portion contains3 to 8 carbon atoms, and R₅ represents a hydrogen atom or an alkylradical; wherein the alkyl radicals and portions are in the form of astraight or branched chain and contain, unless otherwise stated, 1 to 4carbon atoms.
 12. A pharmaceutical composition, comprising at least onederivative compound of formula (I) according to claim 1 and one or morecompatible and pharmaceutically acceptable diluents or adjuvants.
 13. Amethod for treating an infection, comprising administering to a patientin need of said treatment an effective amount of a derivative compoundof formula (I) as claimed in claim
 1. 14. The method according to claim13, wherein the infection is caused by a gram-positive microbe.
 15. Themethod according to claim 14, wherein the gram-positive microbe is aStaphylococcus aureus strain.
 16. The method according to claim 14,wherein the gram-positive microbe is a Streptococcus pneumoniae strain.17. The method according to claim 14, wherein the gram-positive microbeis a Enterococcus faecium strain.
 18. The method according to claim 13,wherein the infection is caused by a gram-negative microbe.
 19. Themethod according to claim 18, wherein the gram-negative microbe is aStaphylococcus aureus strain.
 20. A method according to claim 18,wherein the gram-negative microbe is a Moraxella catharrhalis strain.